Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses

ABSTRACT

Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

RELATED APPLICATIONS

[0001] This application claims the benefit of provisional applicationNo. 60/068,393 filed Dec. 19, 1997.

FIELD OF THE INVENTION

[0002] This invention relates to a novel group of imidazole compounds,processes for the preparation thereof, the use thereof in treatingcytokine mediated diseases and pharmaceutical compositions for use insuch therapy.

BACKGROUND OF THE INVENTION

[0003] Intracellular signal transduction is the means by which cellsrespond to extracellular stimuli. Regardless of the nature of the cellsurface receptor (e.g. protein tyrosine kinase or seven-transmembraneG-protein coupled), protein kinases and phosphatases along withphopholipases are the essential machinery by which the signal is furthertransmitted within the cell [Marshall, J. C. Cell, 80, 179-278 (1995)].Protein kinases can be categorized into five classes with the two majorclasses being, tyrosine kinases and serine/threonine kinases dependingupon whether the enzyme phosphorylates its substrate(s) on specifictyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods inEnzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B.M.; eds. vol. 200, Academic Press; San Diego, 1991].

[0004] For most biological responses, multiple intracellular kinases areinvolved and an individual kinase can be involved in more than onesignaling event. These kinases are often cytosolic and can translocateto the nucleus or the ribosomes where they can affect transcriptionaland translational events, respectively. The involvement of kinases intranscriptional control is presently much better understood than theireffect on translation as illustrated by the studies on growth factorinduced signal transduction involving MAP/ERK kinase [Marshall, C. J.Cell, 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T.Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735(1995)].

[0005] While many signaling pathways are part of cell homeostasis,numerous cytokines (e.g., IL-1 and TNF) and certain other mediators ofinflammation (e.g., COX-2, and iNOS) are produced only as a response tostress signals such as bacterial lipopolysaccharide (LPS). The firstindications suggesting that the signal transduction pathway leading toLPS-induced cytokine biosynthesis involved protein kinases came fromstudies of Weinstein [Weinstein, et al., J. Immunol. 151, 3829(1993)]but the specific protein kinases involved were not identified. Workingfrom a similar perspective, Han [Han, et al., Science 265, 808(1994)]identified murine p38 as a kinase which is tyrosine phosphorylated inresponse to LPS. Definitive proof of the involvement of the p38 kinasein LPS-stimulated signal transduction pathway leading to the initiationof proinflammatory cytokine biosynthesis was provided by the independentdiscovery of p38 kinase by Lee [Lee; et al., Nature, 372, 739(1994)] asthe molecular target for a novel class of anti-inflammatory agents. Thediscovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism ofaction of a class of anti-inflammatory compounds for which SK&F 86002was the prototypic example. These compounds inhibited IL-1 and TNFsynthesis in human monocytes at concentrations in the low uM range [Lee,et al., Int. J. Immunopharmac. 10(7), 835(1988)] and exhibited activityin animal models which are refractory to cyclooxygenase inhibitors [Lee;et al., Annals N.Y. Acad. Sci., 696, 149(1993)].

[0006] It is now firmly established that CSBP/p38 is a one of severalkinases involved in a stress-response signal transduction pathway whichis parallel to and largely independent of the analogousmitogen-activated protein kinase (MAP) kinase cascade (FIG. 1). Stresssignals, including LPS, pro-inflammatory cytokines, oxidants, UV lightand osmotic stress, activate kinases upstream from CSBP/p38 which inturn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resultingin CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have beenidentified as downstream substrates of CSBP/p38 which in turnphosphorylate heat shock protein Hsp 27 (FIG. 2). It is not yet knownwhether MAPKAP-2, MAPKAP-3, Mnk1 or Mnk2 are involved in cytokinebiosynthesis or alternatively that inhibitors of CSBP/p38 kinase mightregulate cytokine biosynthesis by blocking a yet unidentified substratedownstream from CSBP/p38 [Cohen, P. Trends Cell Biol., 353-361(1997)].

[0007] What is known, however, is that in addition to inhibiting IL-1and TNF, CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) alsodecrease the synthesis of a wide variety of pro-inflammatory proteinsincluding, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinasehave also been shown to suppress the TNF-induced expression of VCAM-1 onendothelial cells, the TNF-induced phosphorylation and activation ofcytosolic PLA2 and the IL-1-stimulated synthesis of collagenase andstromelysin. These and additional data demonstrate that CSBP/p38 isinvolved not only cytokine synthesis, but also in cytokine signaling[CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol.,353-361(1997)].

[0008] Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) arebiological substances produced by a variety of cells, such as monocytesor macrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

[0009] There are many disease states in which excessive or unregulatedIL-1 production is implicated in exacerbating and/or causing thedisease. These include rheumatoid arthritis, osteoarthritis, endotoxemiaand/or toxic shock syndrome, other acute or chronic inflammatory diseasestates such as the inflammatory reaction induced by endotoxin orinflammatory bowel disease; tuberculosis, atherosclerosis, muscledegeneration, cachexia, psoriatic arthritis, Reiter's syndrome,rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, andacute synovitis. Recent evidence also links IL-1 activity to diabetesand pancreatic β cells [review of the biological activities which havebeen attributed to IL-1 Dinarello, J. Clinical Immunology, 5 (5),287-297 (1985)].

[0010] Excessive or unregulated TNF production has been implicated inmediating or exacerbating a number of diseases including rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

[0011] Interleukin-8 (IL-8) is a chemotactic factor produced by severalcell types including mononuclear cells, fibroblasts, endothelial cells,and keratinocytes. Its production from endothelial cells is induced byIL-1, TNF, or lipopolysachharide (LPS). IL-8 stimulates a number offunctions in vitro. It has been shown to have chemoattractant propertiesfor neutrophils, T-lymphocytes, and basophils. In addition it induceshistamine release from basophils from both normal and atopic individualsas well as lysozomal enzyme release and respiratory burst fromneutrophils. IL-8 has also been shown to increase the surface expressionof Mac-1 (CD11b/CD 18) on neutrophils without de novo protein synthesis,this may contribute to increased adhesion of the neutrophils to vascularendothelial cells. Many diseases are characterized by massive neutrophilinfiltration. Conditions associated with an increased in IL-8 production(which is responsible for chemotaxis of neutrophil into the inflammatorysite) would benefit by compounds which are suppressive of IL-8production.

[0012] IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

[0013] Inhibition of signal transduction via CSBP/p38, which in additionto IL-1, TNF and IL-8 described above is also required for the synthesisand/or action of several additional pro-inflammatory proteins (i.e.,IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be ahighly effective mechanism for regulating the excessive and destructiveactivation of the immune system. This expectation is supported by thepotent and diverse anti-inflammatory activities described for CSBP/p38kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3):1453-1461.(1996); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996)].

[0014] There remains a need for treatment, in this field, for compoundswhich are cytokine suppressive anti-inflammatory drugs, i.e. compoundswhich are capable of inhibiting the CSBP/p38/RK kinase.

SUMMARY OF THE INVENTION

[0015] This invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.

[0016] Another aspect of the present invention relates to a method oftreating a CSBP/RK/p38 kinase mediated disease, in a mammal in needthereof which comprises administering to said mammal an effective amountof a compound of Formula (I).

[0017] This invention also relates to a method of inhibiting cytokinesand the treatment of a cytokine mediated disease, in a mammal in needthereof which comprises administering to said mammal an effective amountof a compound of Formula (I).

[0018] This invention more specifically relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I).

[0019] This invention more specifically relates to a method ofinhibiting the production of IL-8 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I).

[0020] This invention more specifically relates to a method ofinhibiting the production of TNF in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I).

[0021] Accordingly, the present invention provides for compound ofFormula (I):

[0022] R₁ is 4-pyridazinyl, or a 1,2,4-triazin-5-yl ring, which ring issubstituted with NHR_(a) and optionally substituted with an additional,independent, substituent of C₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆alkyl substituted amino, N(R₁₀)C(O)R_(b) or NHR_(a);

[0023] R_(a) is aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl, wherein each of these moietiesmay be optionally substituted;

[0024] R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl;

[0025] R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, whichis optionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃, S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, (CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃,NR₁₀S(O)_(m′)R₈, NR₁₀S(O)_(m′)NR₇R₁₇, ZC(Z)R₃ or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

[0026] v is 0, or an integer having a value of 1 or 2;

[0027] m is 0, or the integer 1 or 2;

[0028] m′ is an integer having a value of 1 or 2,

[0029] m″ is 0, or an integer having a value of 1 to 5;

[0030] R₂ is —(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl,C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl-C₁₋₁₀-alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroaryl-C₁₋₁₀-alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈, (CR₁₀R₂₀)_(n)S(O)_(m)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₁OR₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR_(10, 5)-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups may be optionallysubstituted;

[0031] n is an integer having a value of 1 to 10;

[0032] n′ is 0, or an integer having a value of 1 to 10;

[0033] Z is oxygen or sulfur;

[0034] R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

[0035] R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —SOR₅ being —SOH;

[0036] R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroaryl₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0037] R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄alkyl or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅;

[0038] R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄;wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;

[0039] R₉ is hydrogen, C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally substituted aryl or optionally substitutedaryl-C₁₋₄ alkyl;

[0040] R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄alkyl;

[0041] R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

[0042] R₁₂ is hydrogen or R₁₆;

[0043] R₁₃ and R₁₄ is each independently selected from hydrogen oroptionally substituted C₁₋₄ alkyl, optionally substituted aryl oroptionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogenwhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

[0044] R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl;

[0045] R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇cycloalkyl;

[0046] R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,aryl₁₋₁₀alkyl, heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl orheteroaryl₁₋₁₀alkyl;

[0047] R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; or apharmaceutically acceptable salt thereof.

[0048] This invention also relates to a novel synthesis for compounds ofFormula (A), as described herein by solid phase synthesis.

[0049] This invention also relates to novel compounds, pharmaceuticalcompositions thereof, and their use in the treatment of CSBP/RK/p38kinase mediated diseases, in a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0050] In Formula (I), suitable R₁ moieties a 4-pyridazinyl,1,2,4-triazin-5-yl ring. The R₁ moiety is substituted with NHR_(a),wherein R_(a) is aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclic C₁₋₆alkyl, heteroaryl, or heteroaryl C₁₋₆alkyl; and wherein each of thesemoieties may be optionally substituted.

[0051] When R_(a) is aryl, it is preferably phenyl or naphthyl. WhenR_(a) is aryl alkyl, it is preferably benzyl or napthylmethyl. WhenR_(a) is heterocyclic or heterocyclic alkyl moiety the heterocycle ispreferably pyrrolindinyl, piperidine, morpholino, tetrahydropyran,tetrahydrothiopyranyl, tetrahydrothiopyransulfinyl,tetrahydrothiopyransulfonyl, pyrrolindinyl, or piperonyl, morepreferably piperidine.

[0052] When R_(a) is a heteroaryl or heteroaryl alkyl, it is heteroarylis preferably imidazole, indole, pyrrole, pyrazole, furan, thiophene,quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole,thiazole, thiadiazole, triazole, or benzimidazole, more preferablyimidazole, or indole.

[0053] As noted above, the aryl, heterocyclic and heteroaryl rings maybe optionally substituted, one or more times, preferably 1 to 3 times,independently, by halogen; C₁₋₄ alkyl, such as methyl, ethyl, propyl,isopropyl, or t-butyl; halosubstituted C₁₋₄ alkyl, such as CF₃; hydroxy;hydroxy substituted C₁₋₄ alkyl; C₁₋₄ alkoxy, such as methoxy or ethoxy;halosubstituted C₁₋₄ alkoxy, such as OCF₂CF₁H or OCF₃; S(O)malkyl andS(O)m aryl (wherein in is 0, 1, or 2); C(O)OR₁₁, such as C(O)C₁₋₄ alkylor C(O)OH moieties; C(O)R₁₁; OC(O)R₁₈, wherein the R₁₈ moiety may beoptionally substituted as herein described below; O—(CH₂)s—O—, such asin a ketal or dioxyalkylene bridge and s is an integer of 1 to 3; amino;mono- and di-C₁₋₆ alkyl substituted amino; N(R₁₀)C(O)R_(b); anN-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₁₅;optionally substituted aryl, such as phenyl; or an optionallysubstituted aryl C₁₋₄ alkyl, such as benzyl or phenethyl.

[0054] Suitably, in compounds of Formula (I), R_(b) is hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclyl, or heterocyclylC₁₋₄ alkyl.

[0055] Suitable R_(a) groups include, benzyl, halosubstituted benzyl,napthylmethyl, phenyl, halosubstituted phenyl, morpholinopropyl,imidazole propyl, ethyl-1-piperidine-carboxylate, piperonyl,piperidin-4-yl, alkyl substituted piperidine, such as 1-methylpiperidine, or 2,2,6,6-tetramethylpiperidin-4-yl, chlorotryptamine,tetrahydrothiopyranyl, ethyl-N—C(O)O t-butyl, propylethoxy,2-aminoethyl, propylimidazole.

[0056] It is recognized that the R₁ group may additionally besubstituted by C₁₋₄ alkyl, halo, OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylsulfinyl, CH₂OR₁₂, amino, mono- and di-C₁₋₆ alkylsubstituted amino,N(R₁₀)C(O)R_(b), NHR_(a) or an N-heterocyclyl ring which ring has from 5to 7 members and optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₁₅. Suitably, when the additional group isother than a dialkylsubstituted amino.

[0057] When the additional R₁ optional substituent is N(R₁₀)C(O) R_(b),R_(b) is preferably C₁₋₆ alkyl; preferably R₁₀ is hydrogen. It is alsorecognized that the R_(b) moieties, in particular the C₁₋₆ alkyl groupmay be optionally substituted, preferably from one to three times,preferably with halogen, such as fluorine, as in trifluoromethyl ortrifluoroethyl.

[0058] Suitably, R₄ is phenyl, naphth-1-yl or naphth-2-yl, or aheteroaryl, which is optionally substituted by one or two substituents.More preferably R₄ is a phenyl or naphthyl ring. Suitable substitutionsfor R₄ when this is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or6-naphth-2-yl moiety are one or two substituents each of which areindependently selected from halogen, SR₅, SOR₅, OR₁₂, CF₃, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀, and for other positions of substitution on theserings preferred substitution is halogen, S(O)_(m)R₃, OR₃, CF₃,(CR₁₀R₂₀)_(m″)NR₁₃R₁₄, NR₁₀C(Z)R₃ and NR₁₀S(O)_(m)R₈. Preferredsubstituents for the 4-position in phenyl and naphth-1-yl and on the5-position in naphth-2-yl include halogen, especially fluoro and chloroand —SR₅ and —SOR₅ wherein R₅ is preferably a C₁₋₂ alkyl, morepreferably methyl; of which the fluoro and chloro is more preferred, andmost especially preferred is fluoro. Preferred substituents for the3-position in phenyl and naphth-1-yl rings include: halogen, especiallyfluoro and chloro; OR₃, especially C₁₋₄ alkoxy; CF₃, NR₁₀R₂₀, such asamino; NR₁₀C(Z)R₃, especially NHCO(C₁₋₁₀ alkyl); NR₁₀S(O)_(m)R₈,especially NHSO₂(C₁₋₁₀ alkyl), and SR₃ and SOR₃ wherein R₃ is preferablya C₁₋₂ alkyl, more preferably methyl. When the phenyl ring isdisubstituted preferably it is two independent halogen moieties, such asfluoro and chloro, preferably di-chloro and more preferably in the3,4-position. It is also preferred that for the 3-position of both theOR₃ and ZC(Z)R₃ moieties, R₃ may also include hydrogen.

[0059] Preferably, the R₄ moiety is an unsubstituted or substitutedphenyl moiety. More preferably, R₄ is phenyl or phenyl substituted atthe 4-position with fluoro and/or substituted at the 3-position withfluoro, chloro, C₁₋₄ alkoxy, methane-sulfonamido or acetamido, or R₄ isa phenyl di-substituted at the 3,4-position independently with chloro orfluoro, more preferably chloro. Most preferably, R₄ is a 4-fluorophenyl.

[0060] In Formula (I), Z is oxygen or sulfur, preferably oxygen.

[0061] Suitably, R₂ is (CR₁₀R₂₀)_(n′)OR₉, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NO₂, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈,(CR₁₀R₂₀)_(n)S(O)_(m),NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₁₁,(CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁, (CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)NR₁₀R₉, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁, (CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀,5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein thecycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic, and heterocyclic alkyl moieties may beoptionally substituted; wherein n is an integer having a value of 1 to10, m is 0, or the integer 1 or 2; n′ is 0, or an integer having a valueof 1 to 10; and m′ is an integer having a value of 1 or 2. Preferably nis 1 to 4.

[0062] When R₂ is an optionally substituted heterocyclyl the ring ispreferably a morpholino, pyrrolidinyl, or a piperidinyl group. When thering is optionally substituted the substituents may be directly attachedto the free nitrogen, such as in the piperidinyl group or pyrrole ring,or on the ring itself. Preferably the ring is a piperidine or pyrrole,more preferably piperidine. The heterocyclyl ring may be optionallysubstituted one to four times independently by halogen; C₁₋₄ alkyl;aryl, such as phenyl; aryl alkyl, such as benzyl—wherein the aryl oraryl alkyl moieties themselves may be optionally substituted (as in thedefinition section below); C(O)OR₁₁, such as the C(O)C₁₋₄ alkyl orC(O)OH moieties; C(O)H; C(O)C₁₋₄ alkyl, hydroxy substituted C₁₋₄ alkyl,C₁₋₄ alkoxy, S(O)_(m)C₁₋₄ alkyl (wherein m is 0, 1, or 2), NR₁₀R₂₀(wherein R₁₀ and R₂₀ are independently hydrogen or C₁₋₄alkyl).

[0063] Preferably if the ring is a piperidine, the ring is attached tothe imidazole at the 4-position, and the substituents are directly onthe available nitrogen, i.e. a 1-Formyl-4-piperidine,1-benzyl-4-piperidine, 1-methyl-4-piperidine,1-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkylgroup and the ring is attached in the 4-position, it is preferablysubstituted in the 2- or 6-position or both, such as2,2,6,6-tetramethyl-4-piperidine. Similarly, if the ring is a pyrrole,the ring is attached to the imidazole at the 3-position, and thesubstituents are all directly on the available nitrogen.

[0064] When R₂ is an optionally substituted heterocyclyl C₁₋₁₀ alkylgroup, the ring is preferably a morpholino, pyrrolidinyl, or apiperidinyl group. Preferably this alkyl moiety is from 1 to 4, morepreferably 3 or 4, and most preferably 3, such as in a propyl group.Preferred heterocyclic alkyl groups include but are not limited to,morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, andpiperidinyl propyl moieties. The heterocyclic ring herein is alsooptionally substituted in a similar manner to that indicated above forthe direct attachment of the heterocyclyl.

[0065] When R₂ is an optionally substituted C₃₋₇cycloalkyl, or anoptionally substituted C₃₋₇cycloalkyl C₁₋₁₀ alkyl, the cycloalkyl groupis preferably a C₄ or C₆ ring, most preferably a C₆ ring, which ring isoptionally substituted. The cycloalkyl ring may be optionallysubstituted one to three times independently by halogen, such asfluorine, chlorine, bromine or iodine; hydroxy; C₁₋₁₀ alkoxy, such asmethoxy or ethoxy; S(O)_(m) alkyl, wherein m is 0, 1, or 2, such asmethyl thio, methylsulfinyl or methyl sulfonyl; S(O)_(m) aryl; cyano,nitro, amino, mono & di-substituted amino, such as in the NR₇R₁₇ group,wherein R₇ and R₁₇ are as defined in Formula (I); N(R₁₀)C(O)R₁₈;preferably N(R₁₀)C(O)X₁ (wherein R₁₀ is as defined for Formula (I)), andX₁ is C₁₋₄ alkyl, aryl or arylC₁₋₄alkyl); C₁₋₁₀ alkyl, such as methyl,ethyl, propyl, isopropyl, or t-butyl; optionally substituted alkylwherein the substituents are halogen, (such as CF₃), hydroxy, nitro,cyano, amino, mono & di-C₁₋₄ alkyl substituted amino; S(O)_(m) alkyl andS(O)_(m) aryl, wherein m is 0, 1 or 2; optionally substituted alkylene,such as ethylene or propylene; optionally substituted alkyne, such asethyne; C(O)OR₁₁ (wherein R₁₁ is as defined in Formula (I)), such as thefree acid or methyl ester derivative; the group R_(c); C(O)H; ═O;═N—OR₁₁; N(H)—OH (or substituted alkyl or aryl derivatives thereof onthe nitrogen or on the oxime moiety); N(OR_(d))—C(O)—R_(e); optionallysubstituted aryl, such as phenyl; optionally substituted arylC₁₋₄alkyl,such as benzyl of phenethyl; optionally substituted heterocycle orheterocyclic C₁₋₄alkyl, and further these aryl, arylalkyl, heterocyclic,and heterocyclic alkyl moieties may be optionally substituted one to twotimes, independently by halogen, hydroxy, C₁₋₁₀ alkoxy, S(O)_(m) alkyl,cyano, nitro, amino, mono & di-C₁₋₄ alkyl substituted amino, alkyl, orhalosubstituted alkyl.

[0066] Suitably the group R_(c) is a 1,3-dioxyalkylene group of theformula —O—(CH₂)_(S)—O—, wherein s is 1 to 3, preferably s is 2 yieldinga 1,3-dioxyethylene moiety, or ketal functionality.

[0067] Suitably R_(d) is hydrogen, a pharmaceutically acceptable cation,aroyl or a C₁₋₁₀ alkanoyl group.

[0068] Suitably R_(e) is NR₂₁R₂₂; C₁₋₆alkyl; halosubstituted C₁₋₆ alkyl;hydroxy substituted C₁₋₆ alkyl; alkenyl₂₋₆; aryl or heteroaryloptionally substituted by halogen, C₁₋₆ alkyl, halosubstituted C₁₋₆alkyl, hydroxyl, or C₁₋₆ alkoxy.

[0069] Suitably R₂₁ is H or alkyl₁₋₆.

[0070] Suitably R₂₂ is H, alkyl₁₋₆, aryl, benzyl, heteroaryl, alkylsubstituted by halogen or hydroxyl, or phenyl substituted by a memberselected from the group consisting of halo, cyano, alkyl₁₋₁₂, alkoxy1-6, halosubstituted alkyl₁₋₆, alkylthio, alkylsulphonyl, oralkylsulfinyl; or R₂₁ and R₂₂ may together with the nitrogen to whichthey are attached form a ring having 5 to 7 members, which members maybe optionally replaced by a heteroatom selected from oxygen, sulfur ornitrogen. The ring may be saturated or contain more than one unsaturatedbond. Preferably R_(6′) is NR₂₁R₂₂ and R₂₁ and R₂₂ are preferablyhydrogen.

[0071] When the R₂ cycloalkyl moiety is substituted by NR₇R₁₇ group, orNR₇R₁₇C₁₋₁₀ alkyl group, and the R₇ and R₁₇ are as defined in Formula(I), the substituent is preferably an amino, amino alkyl, or anoptionally substituted pyrrolidinyl moiety.

[0072] A preferred ring placement on the cycloalkyl moiety is the4-position, such as in a C₆ ring. When the cycloalkyl ring isdi-substituted it is preferably di-substituted at the 4 position, suchas in:

[0073] wherein R^(1′) and R² are independently the optional substituentsindicated above for R₂ as an optionally substituted cycloalkyl.Preferably, R^(1′) and R^(2′) are hydrogen, hydroxy, alkyl, substitutedalkyl, optionally substituted alkyne, aryl, arylalkyl, NR₇R₁₇, andN(R₁₀)C(O)R₁₈. Suitably, alkyl is C₁₋₄ alkyl, such as methyl, ethyl, orisopropyl; NR₇R₁₇ and NR₇R₁₇ alkyl, such as amino, methylamino,aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl,cyanoethyl, nitroethyl, pyrrolidinyl; aryl such as in phenyl; arylalkyl,such as in benzyl; optionally substituted alkyne, such as ethyne orpropynyl; or together R^(1′) and R^(2′) are a keto functionality.

[0074] When R₂ is (CR₁₀R₂₀)_(n)NR₁₃R₁₄, wherein R₁₃ and R₁₄ areindependently selected from hydrogen, optionally substituted C₁₋₄ alkyl,optionally substituted aryl or an optionally substituted aryl-C₁₋₁₄alkyl, or together with the nitrogen which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉. It isrecognized that in some instances this can yield the same moiety as aheterocyclic C₁₋₁₀ alkyl moiety noted above which is also a suitable R₂variable. Preferably R₁₃ and R₁₄ are independently hydrogen, C₁₋₄ alkyl,preferably methyl, or benzyl. The n term is preferably 1 to 4, morepreferably 3 or 4, and most preferably 3, such as in a propyl group.Preferred groups include, but are not limited to, aminopropyl,(N-methyl-N-benzyl)aminopropyl, (N-Phenylmethyl)amino-1-propyl, ordiethylamino propyl.

[0075] When R₂ is a (CR₁₀R₂₀)_(n)C(Z)OR₁₁ group, R₁₁ is suitablyhydrogen, C₁₋₄ alkyl, especially methyl. The n term is preferably 1 to4, more preferably 2 or 3, such as in an ethyl or propyl group.Preferred groups include, but are not limited to, carboxymethyl-1-butyl,carboxy-1-propyl, or 2-acetoxyethyl.

[0076] When R₂ is a (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈ group m is 0, 1, or 2, andR₁₈ is preferably aryl, especially phenyl, or C₁₋₁₀ alkyl, especiallymethyl. The n term is preferably 1 to 4, more preferably 2 or 3, such asin an ethyl or propyl group.

[0077] When R₂ is a (CR₁₀R₂₀)_(n)OR₁₁ group, R₁₁ is suitably hydrogen,aryl, especially phenyl, or C₁₋₁₀ alkyl, especially methyl or ethyl. Then term is preferably 1 to 4, more preferably 2 or 3, such as in an ethylor propyl group.

[0078] When R₂ is a (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈ group, R₁₈ is suitablyalkyl, especially methyl. The n term is preferably 1 to 4, morepreferably 2 or 3, such as in an ethyl or propyl group.

[0079] When R₂ is a optionally substituted aryl, the aryl is preferablyphenyl. The aryl ring may be optionally substituted one or more times,preferably by one or two substituents, independently selected from C₁₋₄alkyl, halogen, especially fluoro or chloro, (CR₁₀R₂₀)_(t)OR₁₁,(CR₁₀R₂₀)_(t)NR₁₀R₂₀, especially amino or mono- or di-alkylamino(CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, wherein m is 0, 1 or 2; SH,(CR₁₀R₂₀)_(n)NR₁₃R₁₄, NR₁₀C(Z)R₃ (such —NHCO(C₁₋₁₀ alkyl));NR₁₀S(O)_(m)R₈ (such as NHSO₂(C₁₋₁₀ alkyl)); and t is 0, or an integerof 1 to 4. Preferably the phenyl is substituted in the 3 or 4-positionby (CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, and R₁₈ is preferably C₁₋₁₀ alkyl,especially methyl.

[0080] When R₂ is an optionally substituted heteroaryl orheteroarylalkyl group the ring may be optionally substituted one or moretimes, preferably by one or two substituents, independently selectedfrom one or more times, by C₁₋₄ alkyl, halogen, especially fluoro orchloro, (CR₁₀R₂₀)_(t)OR₁₁, (CR₁₀R₂₀)_(t)NR₁₀R₂₀, especially amino ormono- or di-alkylamino —CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, wherein m is 0, 1 or 2;SH, (CR₁₀R₂₀)_(n)—NR₁₃R₁₄, NR₁₀C(Z)R₃ (such NHCO(C₁₋₁₀ alkyl));NR₁₀S(O)_(m)R₈ (such as —NHSO₂(C₁₋₁₀ alkyl)); t is 0, or an integer of 1to 4.

[0081] One skilled in the art would readily recognize that when R₂ is a(CR₁₀R₂₀)_(n)OC(Z)R₁₁, or (CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄ moiety, or anysimilarly substituted group that n is preferably at least 2 which willallow for the synthesis of stable compounds.

[0082] Preferably R₂ is an optionally substituted heterocyclyl ring, andoptionally substituted heterocyclylC₁₋₁₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted C₃₋₇cycloalkyl, anoptionally substituted C₃₋₇cycloalkyl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)C(Z)OR₁₁group, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, an optionally substituted aryl; an optionallysubstituted arylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)C(Z)R₁₁ or(CR₁ or 20)_(n)C(═NOR₆)R₁₁ group.

[0083] More preferably R₂ is an optionally substituted heterocyclylring, and optionally substituted heterocyclylC₁₋₁₀ alkyl, optionallysubstituted aryl, optionally substituted C₃₋₇cycloalkyl, optionallysubstituted C₃₋₇cycloalkyl C₁₋₀ alkyl, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, or(CR₁₀R₂₀)_(n)C(Z)OR₁₁ group. Most preferably R₂ is an optionallysubstituted heterocyclic, heterocyclic C₁₋₄ alkyl, a cycloalkyl or acycloalkyl alkyl.

[0084] More preferably when R₂ is an optionally substituted cycloalkylor cycloalkylalkyl it is a C₄ or C₆ cycloalkyl, cyclopropyl methyl, or acyclohexyl substituted by methyl, phenyl, benzyl, amino, acetamide,aminomethyl, aminoethyl, cyanomethyl, cyanoethyl, hydroxy, nitroethyl,pyrrolidinyl, ethynyl, 1-propynyl, ═O, O—(CH₂)₂O—, ═NOR₁₁, wherein R₁₁is hydrogen, alkyl or aryl, NHOH, or N(OH)—C(O)—NH₂; or when R₂ isheterocyclic, or heterocyclicalkyl, it is morpholinyl butyl, morpholinylpropyl, morpholinylethyl, piperidinyl, N-benzyl-4-piperidinyl,N-methyl-4-piperidinyl, 2,2,6,6-tetramethypiperidinyl, substitutedpiperidine, such as 1-Formyl-4-piperidine, or a1-ethoxycarbonyl-4-piperidine.

[0085] In all instances herein where there is an alkenyl or alkynylmoiety as a substituent group, the unsaturated linkage, i.e., thevinylene or acetylene linkage is preferably not directly attached to thenitrogen, oxygen or sulfur moieties, for instance in OR₃, or for certainR₂ moieties.

[0086] As used herein, “optionally substituted” unless specificallydefined shall mean such groups as halogen, such as fluorine, chlorine,bromine or iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2,such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono &di-C₁₋₄ alkyl substituted amino, such as in the NR₇R₁₇ group; or wherethe R₇R₁₇ may together with the nitrogen to which they are attachedcyclize to form a 5 to 7 membered ring which optionally includes anadditional heteroatom selected from O/N/S; C₁₋₁₀ alkyl, cycloalkyl, orcycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl,t-butyl, etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, suchCF₃; halosubstituted C₁₋₁₀ alkoxy, such OCF₂CF₂H, or OCF₃; an optionallysubstituted aryl, such as phenyl, or an optionally substitutedarylalkyl, such as benzyl or phenethyl, wherein these aryl moieties mayalso be substituted one to two times by halogen; hydroxy; hydroxysubstituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono &di-substituted amino, such as in the NR₇R₁₇ group; alkyl, or CF₃.

[0087] Suitable pharmaceutically acceptable salts are well known tothose skilled in the art and include basic salts of inorganic andorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid,acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalicacid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylicacid, phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of Formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent groupcomprises a carboxy moiety. Suitable pharmaceutically acceptable cationsare well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quaternary ammonium cations.

[0088] The following terms, as used herein, refer to:

[0089] “halo” or “halogens”, include the halogens: chloro, fluoro, bromoand iodo.

[0090] “C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain radicalsof 1 to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

[0091] “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

[0092] “cycloalkenyl” is used herein to mean cyclic radicals, preferablyof 5 to 8 carbons, which have at least one bond including but notlimited to cyclopentenyl, cyclohexenyl, and the like.

[0093] “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

[0094] “aryl”—phenyl and naphthyl;

[0095] “heteroaryl” (on its own or in any combination, such as“heteroaryloxy”, or “heteroaryl alkyl”)—a 5-10 membered aromatic ringsystem in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O or S, such as, but notlimited, to pyrrole, pyrazole, furan, thiophene, quinoline,isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole,thiadiazole, triazole, imidazole, or benzimidazole.

[0096] “heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”)—a saturated or partially unsaturated 4-10 memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, or S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine,tetrahydropyran, or imidazolidine.

[0097] “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₄ alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate.

[0098] “sulfinyl”—the oxide S(O) of the corresponding sulfide, the term“thio” refers to the sulfide, and the term “sulfonyl” refers to thefully oxidized S(O)₂ moiety.

[0099] “aroyl”—a C(O)Ar, wherein Ar is as phenyl, naphthyl, or arylalkyl derivative such as defined above, such group include but are notlimited to benzyl and phenethyl.

[0100] “alkanoyl”—a C(O)C₁₋₁₀ alkyl wherein the alkyl is as definedabove.

[0101] It is recognized that the compounds of the present invention mayexist as stereoisomers, regioisomers, or diastereiomers. These compoundsmay contain one or more asymmetric carbon atoms and may exist in racemicand optically active forms. All of these compounds are included withinthe scope of the present invention.

[0102] Another aspect of the present invention are the novel compoundsexemplified below:

[0103]1-Cyclohexyl-4-(4-fluorophenyl)-5-[(2-phenylamino)pyrimidin-4-yl]imidazole;

[0104] 1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2[N-(3-morpholino)propyl]amino]pyrimidin-4-yl]imidazole;

[0105]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(2-imidazol-4-yl)ethyl]amino]pyrimidin-4-yl]imidazole;

[0106]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3-pyridyl)methyl]amino]pyrimidin-4-yl]imidazole;

[0107]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3,3-diphenyl)propyl]amino]pyrimidin-4-yl]imidazole;

[0108](+/−)-1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(1-methyl-3-phenyl)propyl]amino]pyrimidin-4-yl]imidazole;

[0109]N-4-[[[4-(4-Fluorophenyl)]-5-[[2-[(3-trifluoromethyl)phenyl]amino]]pyrimidine-4-yl]imidazol-4-yl]piperdinyl-N′-[(3-trifluoromethyl)phenyl]urea;

[0110]N-[2-[4-(4-Fluorophenyl)-5-[[2-(3,4-dichlorobenzyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamide;

[0111]N-[2-[4-(4-Fluorophenyl)-5-[[2-(4-methoxybenzylamino)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide;

[0112] 1-Isopropyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;

[0113]1-Cyclopentyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;

[0114]1-[(1-t-Butoxycarbonyl)-4-piperidinyl]-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)amino]pyrimidin-4-yl]imidazole;

[0115]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)amino]pyrimidin-4-yl]imidazole;

[0116]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-5-fluorophenyl)amino]pyrimidin-4-yl]imidazole;

[0117]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenyl)aminopyrimidin-4-yl]imidazole;

[0118]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenyl)amino]pyrimidin-4-yl]imidazole;

[0119]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;

[0120]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenylamino)-pyrimidin-4-yl]imidazole;

[0121]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-methylphenylamino)-pyrimidin-4-yl]imidazole;

[0122]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenylamino)pyrimidin-4-yl]imidazole;

[0123]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenylamino)pyrimidin-4-yl]imidazol;

[0124]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-morpholin-4-ylphenylamino)-pyrimidin-4-yl]imidazole;or

[0125] a pharmaceutically acceptable salt thereof.

[0126] Another aspect of the present invention is the novelpharmaceutical compositions comprising a pharmacuetically acceptablediluent or carrier, and an effective amount of an exemplified compounddefined above.

[0127] Another aspect of the present invention relates to a method oftreating a CSBP/RK/p38 kinase mediated disease, in a mammal in needthereof which comprises administering to said mammal an effective amountof an exemplified compound as described above.

[0128] This invention also relates to a method of inhibiting cytokinesand the treatment of a cytokine mediated disease, in a mammal in needthereof which comprises administering to said mammal an effective amountof an exemplified compound as described above.

[0129] This invention more specifically relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of anexemplified compound as described above.

[0130] This invention more specifically relates to a method ofinhibiting the production of IL-8 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of anexemplified compound as described above.

[0131] This invention more specifically relates to a method ofinhibiting the production of TNF in a mammal in need thereof whichcomprises administering to said mammal an effective amount of anexemplified compound as described above.

[0132] Another aspect of the present invention relates to a process forproducing the exemplified compounds noted above. For simplicity theexemplified compounds are summarized in the table below.

[0133] The present invention relates to an analagous process for makingcompounds of the formula:

wherein: R₂ R_(a) cyclohexyl phenyl cyclohexyl

cyclohexyl

cyclohexyl

cyclohexyl (3,3-diphenyl)propyl cyclohexyl (1-methyl-3-phenyl)propyl

(3-trifluoromethyl)phenyl (3,4-dimethoxybenzamide 3,4-dichlorobenzylethyl ethoxyacetamide-ethyl 4-methoxybenzyl isopropyl phenyl cyclopentylphenyl (1-t-butoxycarbonyl)-4- (2-methyl-4-fluorophenyl) piperidinyl4-pipendinyl (2-methyl-4-fluorophenyl) 4-piperidinyl(2-methyl-5-fluorophenyl) 4-piperidinyl (2,6-dimethylphenyl)4-piperidinyl (2-methylphenyl) 4-fluorophenyl phenyl 4-fluorophenyl(2-methylphenyl) 4-fluorophenyl (2,6-dimethylphenyl) 4-fluorophenyl

[0134] reacting a compound of the formula:

[0135] with a compound of the formula:

[0136] wherein p is 2; Ar is an unsubstituted or substituted aryl; andR_(a) and R₂ are as described above; with a base strong enough todeprotonate the isonitrile moiety of Formula (IIa); and wherein theimine of Formula (III), is formed in situ prior to reaction with Formula(IIa); to yield a compound as defined in the table above. Suitably, theAr is a phenyl optionally substituted by C₁₋₄alkyl, C₁₋₄ alkoxy orhalogen. Preferably, Ar is phenyl or 4-methylphenyl, i.e. a tosylderivative.

[0137] In this process the base is preferably an amine, an amide, acarbonate, a hydride, an alkyl or aryl lithium reagent, or a mono-, di-or tribasic phosphate.

[0138] The imine of this reaction is preferably formed in situ byreacting an aldehyde of the formula:

[0139] wherein R_(a) is as defined above,

[0140] with a primary amine of the formula R₂NH₂, wherein R₂ is asdefined above.

[0141] In this process the formation of the imine in situ may utilizedehydrating conditions as can be found in the numerous patentsreferenced herein. Preferably, solvents used in this proces areN,N-dimethyl-formamide (DMF), halogenated solvents, tetrahydrofuran(THF), dimethylsulfoxide (DMSO), an alcohol, benzene, toluene, MeCN, orDME.

[0142] The intermediates of Formula (II) may suitably be made asdescribed in U.S. Pat. No. 5,739,143, see Scheme VIII; and WO 97/23479.

[0143] In an alternative synthesis to make the novel exmplifiedcompounds of the formula:

wherein: R₂ R_(a) cyclohexyl phenyl cyclohexyl

cyclohexyl

cyclohexyl

cyclohexyl (3,3-diphenyl)propyl cyclohexyl (1-methyl-3-phenyl)propyl

(3-trifluoromethyl)phenyl (3,4-dimethoxybenzamide 3,4-dichlorobenzylethyl ethoxyacetamide-ethyl 4-methoxybenzyl isopropyl phenyl cyclopentylphenyl (1-t-butoxycarbonyl)-4- (2-methyl-4-fluorophenyl) piperidinyl4-piperidinyl (2-methyl-4-fluorophenyl) 4-pipendinyl(2-methyl-5-fluorophenyl) 4-piperidinyl (2,6-dimethylphenyl)4-piperidinyl (2-methylphenyl) 4-fluorophenyl phenyl 4-fluorophenyl(2-methylphenyl) 4-fluorophenyl (2,6-dimethylphenyl) 4-fluorophenyl

[0144] which process comprises

[0145] reacting a compound of the formula:

[0146] with a compound of the formula:

[0147] wherein R is a substituted or unsubstituted C₁₋₄ alkyl; Ar is anunsubstituted or substitued aryl; R₂ is as defined above, and p is =2;

[0148] to yield a compound of the formula:

[0149] wherein R and R₂ are as defined above;

[0150] and using suitable oxidizing conditions to make the correspondingsulfone or sulfoxide derivative; and using suitable displacementconditions reacting the corresponding sulfone or sulfoxide derivativewith the desired activatedNH₂Ra moiety, or a precurser thereof such asthe metal salt, i.e. the activated lithium or aluminum complex, to yielda compound as defined in the table above. Suitably, the Ar is a phenyloptionally substituted by C₁₋₄alkyl, C₁₋₄ alkoxy or halogen. Preferably,Ar is phenyl or 4-methylphenyl, i.e. a tosyl derivative.

[0151] Suitable oxidizing conditions are well known in the art, and maybe found in, for instance U.S. Pat. No. 5,756,499. While it isrecognized that in Scheme VI therein the oxidation and displacement ofthe RS moiety on the pyrimidine takes place prior to the imidazoleformation, but the same general conditions would apply herein. Oxone isa preferred oxidiation reagent to convert the alkylthio deriviative tothe corresponding sulfone, or sulfoxide, or both (Formula IIIa).

[0152] Displacement of the oxidized sulfone or sulfoxide derivative isalso well known in the art. Suitably, activation of the desired aniline(Ra-NH₂) with trimethyl aluminum yields the aluminum amide complex.Reaction of this complex with the oxidizied sulfoxide or sulfone ofFormula (IIIa) will generate the desired compounds herein of Formula(III). Alternatively, the aniline may be reacted with a strong base,such as butyl lithium or LDA directly, and then reacted with thesulfoxide or sulfone will generate the desired compounds herein.

[0153] The novel compounds of Formula (I) and the specificallyexemplified compounds herein may also be obtained by applying varioussynthetic procedures, some of which are described in U.S. Pat. No.5,658,903, U.S. Ser. No. 09/012,946 (now allowed), U.S. Pat. Nos.5,739,143, 5,716,955, and 5,593,992 whose disclosures are incorporatedherein by reference in their entirety.

[0154] An alternative process for preparing the above exemplifiedcompounds, and compounds of Formula (A), as described herein, is byusing solid-phase techniques as shown below.

[0155] In this scheme sodium 2-thiopyrimidine-4-dimethyl acetal (1) canbe treated with Merrifield resin in DMF at room temperature to affordpolymer-bound pyrimidine acetal (2) in nearly quantitative yield.Treatment of 2 with TFA either at room temperature or by heating toreflux efficiently affords polymer-bound aldehyde 3. Condensation of 3with NH₂R₂, wherein R₂ is as defined in formula (I) or (A) affords thecorresponding polymer-bound imines 4. Cycloaddition of 4 withisonitriles of formula (II) in the presence of a strong base such asTDB, which is soluble in an organic solvent which will swell the resinsuch as DMF, affords polymer-bound 2-thiopyrimidinyl-imidazoles 6. Thedesired compound of Formula (A)(8) can be released from the polymer byfirst oxidizing 6 to the corresponding sulfone (7) using, for instance,3-chloroperoxybenzoic acid followed by treatment with NH₂R_(a). In casesin which the amine is aliphatic, the displacement simply requiresstirring the sulfone 7 with the amine at temperatures ranging fromambient to 100° C. Displacement with anilines requires activation with astrong base such as sodium hydride or a lewis acid such astrimethylaluminum followed by heating in an inert solvent such as TUF ortoluene.

[0156] Another aspect of the present invention, therefore, is the novelprocess for preparing 2-thiopyrimidin-4-ylimidazoles derivatives on asolid support, such as a Merrifield resin. This process involves thecycloaddition of a polymer-bound 2-thiopyrimidin-4-yl carboxaldehyde(imines) with suitable isonitriles (II) as depicted in Scheme I and thecharacteristics of which have been described previously, in U.S. Pat.No. 5,658,903, to give polymer-bound 2-thiopyrimidine-4ylimidazoles.This is followed by cycloaddition of the polymer-bound imines with asuitable isonitrile (II) which can be conducted at temperatures from −10to 100° C., but requires a solvent, such as CH₂Cl₂, which will swell theresin, and a base which is soluble in this solvent, such as TBD. Thereaction may also be conducted using other solvents which swell theresin such as DMF, dioxane or THF. Other organic soluble bases such asthe heterocyclic bases DBU and DBN as well as primarily amines such ast-butylamine may be substituted for TBD. Use of conditions such as K₂CO₃in DMF, which work well in solution, fail to effect cycloaddition withthe polymer-bound imines. Liberation of the polymer-bound2-thiopyrimidine-4ylimidazoles to give 2-aminopyrimidin-4-ylimidazolederivatives of Formula (I) or (A) can be accomplished by the followingtwo step process: 1) Polymer-bound 2-thiopyrimidine-4-yl imidazoles canbe oxidized to either the corresponding sulfoxides or sulfones (or amixture of the two) by treatment of the polymer-bound sulfide with anappropriate organic soluble oxidant such as 3-chloro-peroxybenzoic acidor and organic soluble oxone, such as tetrabutylammonium oxone, in asolvent which will swell the resin, such as CH₂Cl₂; and 2) Treatment ofeither the sulfoxides or sulfones with amines of the formula R_(a)NH₂,wherein R_(a) is defined in Formula (I) or (A) at temperatures rangingfrom about 0 to 120° C. , or even higher to 150° C. affords compounds ofFormula (A).

[0157] Preparation of polymer-bound 2-thiopyrimidin-4-ylcarboxaldehyde(imines) require, first of all, preparation ofpolymer-bound 2-thiopyrimidine-4-yl carboxaldehyde dimethyl acetal. Thesodium salt of 2-thiopyrimidine-4-yl carboxaldehyde dimethyl acetal canbe prepared as outlined in the Scheme, herein. Stirring or shaking thesalt with Merrifield resin at temperatures ranging from 10 to 100° C. ina solvent which both swells the resin and dissolves the salt, forinstance DMF, affords a nearly quantitative loading of the pyrimidine onthe resin. The dimethylacetal can be hydrolyzed to the aldehyde with outeffecting the thio linker by reaction at temperatures ranging from 20 to80° C. with a strong acid, such as TFA, which can also serve to swellthe resin. Conversion of the polymer-bound aldehyde to the desiredimines can be achieved by simply stirring the desired amine (R₂NH₂) asindicated in Formula (I) or (A) with polymer-bound aldehyde in an inertresin-swelling solvent such as CH₂Cl₂ at temperatures ranging from 0 to60° C.

[0158] Pharmaceutically acid addition salts of compounds of Formula (I)or (A) may be obtained in known manner, for example by treatment thereofwith an appropriate amount of acid in the presence of a suitablesolvent.

[0159] Compounds of Formula (A) are described as compounds of Formula(I) in U.S. Pat. No. 5,658,903, and are the same as those described forFormula (I) herein but for the substitution of a 4-pyrimidinyl ring forthe R₁ pyridazin-4-yl or 1,2,4-triazin-5-yl substituens defined herein.It is also recognized that the exemplified compounds above, all fallwithin the genus of compounds described as Formula (A).

[0160] Compounds of Formula (A) are represented by the structure:

[0161] wherein

[0162] R₁ is 4-pyrimidinyl ring which ring is substituted with NHR_(a)and optionally substituted with an additional, independent, substituentof C₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆ alkyl substituted amino,N(R₁₀)C(O)R_(b) or NHR_(a);

[0163] R_(a) is hydrogen, alkyl, optionally substituted alkyl, aryl,arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl, wherein each of the aryl, heterocyclic andheteroaryl containing moieties may be optionally substituted;

[0164] R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl;

[0165] R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, whichis optionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃,S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl,(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃, NR₁₀S(O)_(m)R₈, NR₁₀S(O)_(m), NR₇R₁₇, ZC(Z)R₃or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

[0166] v is 0, or an integer having a value of 1 or 2;

[0167] m is 0, or the integer 1 or 2;

[0168] m′ is an integer having a value of 1 or 2,

[0169] m″ is 0, or an integer having a value of 1 to 5;

[0170] R₂ is —(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl,C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl-₁₋₁₀-alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroaryl-₁₋₁₀-alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈, (CR₁₀R₂₀)_(n)S(O)_(m),NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₁OR₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups may be optionallysubstituted;

[0171] n is an integer having a value of 1 to 10;

[0172] n940 is 0, or an integer having a value of 1 to 10;

[0173] Z is oxygen or sulfur;

[0174] R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

[0175] R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties SR₅ being SNR₇R₁₇ and SORs being SOH;

[0176] R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroaryl₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

[0177] R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄alkyl or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅;

[0178] R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroaryC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄;wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;

[0179] R₉ is hydrogen, C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally substituted aryl or optionally substitutedaryl-C₁₋₄ alkyl;

[0180] R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄alkyl;

[0181] R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

[0182] R₁₂ is hydrogen or R₁₆;

[0183] R₁₃ and R₁₄ is each independently selected from hydrogen oroptionally substituted C₁₋₄ alkyl, optionally substituted aryl oroptionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogenwhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

[0184] R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl;

[0185] R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇cycloalkyl;

[0186] R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,aryl₁₋₁₀alkyl, heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl orheteroaryl₁₋₁₀alkyl;

[0187] R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl;

[0188] or a pharmaceutically acceptable salt thereof.

[0189] Methods of Treatment

[0190] The compounds of Formula (I), or the above noted exemplifiedcompounds herein, or a pharmaceutically acceptable salt thereof can beused in the manufacture of a medicament for the prophylactic ortherapeutic treatment of any disease state in a human, or other mammal,which is exacerbated or caused by excessive or unregulated cytokineproduction by such mammal's cell, such as but not limited to monocytesand/or macrophages.

[0191] For purposes herein in the Method of Treatment section, compoundsof Formula (I) and the novel exemplified compounds are usedinterchangeably. The methods of formulation, dosage forms, diseasemanagement, etc. are the same for both formulas. For instance,“Compounds of Formula (I) are capable . . . ” is also the same asstating: “Compounds of Formula (I) and the novel compounds asexemplified herein, are capable . . . ”.

[0192] Compounds of Formula (I) are capable of inhibitingproinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF and aretherefore of use in therapy. IL-1, IL-6, IL-8 and TNF affect a widevariety of cells and tissues and these cytokines, as well as otherleukocyte-derived cytokines, are important and critical inflammatorymediators of a wide variety of disease states and conditions. Theinhibition of these pro-inflammatory cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

[0193] Accordingly, the present invention provides a method of treatinga cytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

[0194] Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandinsaffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

[0195] Accordingly, the present invention provides a method ofinhibiting the synthesis of COX-2 which comprises administering aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. The present invention also provides for amethod of prophylaxis treatment in a human, or other mammal, byinhibition of the synthesis of the COX-2 enzyme.

[0196] A new member of the MAP kinase family, alternatively termed CSBP,p38, or RK, has been identified independently by several laboratoriesrecently. Activation of this novel protein kinase via dualphosphorylation has been observed in different cell systems uponstimulation by a wide spectrum of stimuli, such as physicochemicalstress and treatment with lipopolysaccharide or proinflammatorycytokines such as interleukin-1 and tumor necrosis factor. The cytokinebiosynthesis inhibitors, of the present invention, compounds of Formula(T), have been determined to be potent and selective inhibitors ofCSBP/p38/RK kinase activity. These inhibitors are of aid in determiningthe signaling pathways involvement in inflammatory responses. Inparticular, for the first time a definitive signal transduction pathwaycan be prescribed to the action of lipopolysaccharide in cytokineproduction in macrophages.

[0197] The cytokine inhibitors were subsequently tested in a number ofanimal models for anti-inflammatory activity. Model systems were chosenthat were relatively insensitive to cyclooxygenase inhibitors in orderto reveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance are the compounds effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993). B Ann. N.Y. Acad. Sci. 696, 149-170.

[0198] Another aspect of the present invention, therefore, is thetreatment of a CSBP/RK/p38 kinase mediated disease, in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I). Suitable diseases, include thosementioned herein for IL-1, IL-6, IL-8 and TNF and more specificallythose disease which are CSBP/RK/p38 kinase mediated diseases. Theseinclude, but are not limited to rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, gouty arthritis and other arthriticconditions, sepsis, septic shock, endotoxic shock, gram negative sepsis,toxic shock syndrome, asthma, adult respiratory distress syndrome,stroke, reperfusion injury, CNS injuries, such as neurotrauma andischemia, including both open and closed head injuries), psoriasis,restenosis, such as occurs following coronary angioplasty, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcososis, bone resorption diseases, osteoporosis, graft vs. hostreaction, allograft rejections, Crohn's disease, ulcerative colitis orany other anti-inflammatory bowel disease (IBD), or pyresis.

[0199] CNS injuries as defined herein include both open or penetratinghead trauma, such as by surgery, or a closed head trauma injury, such asby an injury to the head region. Also included within this definition isischemic stroke, particularly to the brain area.

[0200] Ischemic stroke may be defined as a focal neurologic disorderthat results from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. The role of inflammatory cytokines in thisare has been emerging and the present invention provides a mean for thepotential treatment of these injuries. Relatively little treatment, foran acute injury such as these has been available.

[0201] TNF-α is a cytokine with proinflammatory actions, includingendothelial leukocyte adhesion molecule expression. Leukocytesinfiltrate into ischemic brain lesions and hence compounds which inhibitor decrease levels of TNF would be useful for treatment of ischemicbrain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp. 1481-88 (1994)whose disclosure is incorporated herein by reference.

[0202] Models of closed head injuries and treatment with mixed 5-LO/COagents is discussed in Shohami et al., J. of Vaisc & Clinical Physiologyand Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure isincorporated herein by reference. Treatment which reduced edemaformation was found to improve functional outcome in those animalstreated.

[0203] In particular, compounds of Formula (I) or a pharmaceuticallyacceptable salt thereof are of use in the prophylaxis or therapy of anydisease state in a human, or other mammal, which is exacerbated by orcaused by excessive or unregulated IL-1, IL-8 or TNF production by suchmammal's cell, such as, but not limited to, monocytes and/ormacrophages.

[0204] Accordingly, in another aspect, this invention relates to amethod of inhibiting the production of IL-1 in a mammal in need thereofwhich comprises administering to said mammal an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0205] There are many disease states in which excessive or unregulatedIL-1 production is implicated in exacerbating and/or causing thedisease. These include rheumatoid arthritis, osteoarthritis, stroke,endotoxemia and/or toxic shock syndrome, other acute or chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis,muscle degeneration, multiple sclerosis, cachexia, bone resorption,psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,traumatic arthritis, rubella arthritis and acute synovitis. Recentevidence also links IL-1 activity to diabetes, pancreatic 1 cells andAlzheimer's disease.

[0206] In a further aspect, this invention relates to a method ofinhibiting the production of TNF in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

[0207] Excessive or unregulated TNF production has been implicated inmediating or exacerbating a number of diseases including rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcoisosis, bone resorption diseases,such as osteoporosis, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDSrelated complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis and pyresis.

[0208] Compounds of Formula (I) are also useful in the treatment ofviral infections, where such viruses are sensitive to upregulation byTNF or will elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

[0209] Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

[0210] The compounds of Formula (I) may also be used topically in thetreatment or prophylaxis of topical disease states mediated by orexacerbated by excessive cytokine production, such as by IL-1 or TNFrespectively, such as inflamed joints, eczema, psoriasis and otherinflammatory skin conditions such as sunburn; inflammatory eyeconditions including conjunctivitis; pyresis, pain and other conditionsassociated with inflammation.

[0211] Compounds of Formula (I) have also been shown to inhibit theproduction of IL-8 (Interleukin-8, NAP). Accordingly, in a furtheraspect, this invention relates to a method of inhibiting the productionof IL-8 in a mammal in need thereof which comprises administering tosaid mammal an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

[0212] There are many disease states in which excessive or unregulatedIL-8 production is implicated in exacerbating and/or causing thedisease. These diseases are characterized by massive neutrophilinfiltration such as, psoriasis, inflammatory bowel disease, asthma,cardiac and renal reperfusion injury, adult respiratory distresssyndrome, thrombosis and glomerulonephritis. All of these diseases areassociated with increased IL-8 production which is responsible for thechemotaxis of neutrophils into the inflammatory site. In contrast toother inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the uniqueproperty of promoting neutrophil chemotaxis and activation. Therefore,the inhibition of IL-8 production would lead to a direct reduction inthe neutrophil infiltration.

[0213] The compounds of Formula (I) are administered in an amountsufficient to inhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF,production such that it is regulated down to normal levels, or in somecase to subnormal levels, so as to ameliorate or prevent the diseasestate. Abnormal levels of IL-1, IL-6, IL-8 or TNF, for instance in thecontext of the present invention, constitute: (i) levels of free (notcell bound) IL-1, IL-6, IL-8 or TNF greater than or equal to 1 picogramper ml; (ii) any cell associated IL-1, WL-6, IL-8 or TNF; or (iii) thepresence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells ortissues in which IL-1, IL-6, IL-8 or TNF, respectively, is produced.

[0214] The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

[0215] As used herein, the term “inhibiting the production of IL-1(IL-6, IL-8 or TNF)” refers to:

[0216] a) a decrease of excessive in vivo levels of the cytokine (IL-1,IL-6, IL-8 or TNF) in a human to normal or sub-normal levels byinhibition of the in vivo release of the cytokine by all cells,including but not limited to monocytes or macrophages;

[0217] b) a down regulation, at the genomic level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

[0218] c) a down regulation, by inhibition of the direct synthesis ofthe cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or

[0219] d) a down regulation, at the translational level, of excessive invivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human tonormal or sub-normal levels.

[0220] As used herein, the term “TNF mediated disease or disease state”refers to any and all disease states in which TNF plays a role, eitherby production of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

[0221] As used herein, the term “cytokine” refers to any secretedpolypeptide that affects the functions of cells and is a molecule whichmodulates interactions between cells in the immune, inflammatory orhematopoietic response. A cytokine includes, but is not limited to,monokines and lymphokines, regardless of which cells produce them. Forinstance, a monokine is generally referred to as being produced andsecreted by a mononuclear cell, such as a macrophage and/or monocyte.Many other cells however also produce monokines, such as natural killercells, fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta(TNF-β).

[0222] As used herein, the term “cytokine interfering” or “cytokinesuppressive amount” refers to an effective amount of a compound ofFormula (I) which will cause a decrease in the in vivo levels of thecytokine to normal or sub-normal levels, when given to a patient for theprophylaxis or treatment of a disease state which is exacerbated by, orcaused by, excessive or unregulated cytokine production.

[0223] As used herein, the cytokine referred to in the phrase“inhibition of a cytokine, for use in the treatment of a HIV-infectedhuman” is a cytokine which is implicated in (a) the initiation and/ormaintenance of T cell activation and/or activated T cell-mediated HIVgene expression and/or replication and/or (b) any cytokine-mediateddisease associated problem such as cachexia or muscle degeneration.

[0224] As TNF-β (also known as lymphotoxin) has close structuralhomology with TNF-α (also known as cachectin) and since each inducessimilar biologic responses and binds to the same cellular receptor, bothTNF-α and TNF-β are inhibited by the compounds of the present inventionand thus are herein referred to collectively as “TNF” unlessspecifically delineated otherwise.

[0225] In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be Formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

[0226] Compounds of Formula (I), pharmaceutically acceptable saltsthereof and pharmaceutical compositions incorporating such mayconveniently be administered by any of the routes conventionally usedfor drug administration, for instance, orally, topically, parenterallyor by inhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the Formulation and not deleterious to the recipient thereof.

[0227] The pharmaceutical carrier employed may be, for example, either asolid or liquid. Exemplary of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like. Similarly, the carrier ordiluent may include time delay material well known to the art, such asglyceryl mono-stearate or glyceryl distearate alone or with a wax.

[0228] A wide variety of pharmaceutical forms can be employed. Thus, ifa solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form or in the form of a trocheor lozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

[0229] Compounds of Formula (I) may be administered topically, that isby non-systemic administration. This includes the application of acompound of Formula (I) externally to the epidermis or the buccal cavityand the instillation of such a compound into the ear, eye and nose, suchthat the compound does not significantly enter the blood stream. Incontrast, systemic administration refers to oral, intravenous,intraperitoneal and intramuscular administration.

[0230] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theFormulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe Formulation.

[0231] Lotions according to the present invention include those suitablefor application to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

[0232] Creams, ointments or pastes according to the present inventionare semi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

[0233] Drops according to the present invention may comprise sterileaqueous or oily solutions or suspensions and may be prepared bydissolving the active ingredient in a suitable aqueous solution of abactericidal and/or fungicidal agent and/or any other suitablepreservative, and preferably including a surface active agent. Theresulting solution may then be clarified by filtration, transferred to asuitable container which is then sealed and sterilized by autoclaving ormaintaining at 98-100° C. for half an hour. Alternatively, the solutionmay be sterilized by filtration and transferred to the container by anaseptic technique. Examples of bactericidal and fungicidal agentssuitable for inclusion in the drops are phenylmercuric nitrate oracetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidineacetate (0.01%). Suitable solvents for the preparation of an oilysolution include glycerol, diluted alcohol and propylene glycol.

[0234] Compounds of formula (I) may be administered parenterally, thatis by intravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

[0235] For all methods of use disclosed herein for the compounds ofFormula (I), the daily oral dosage regimen will preferably be from about0.01 to about 80 mg/kg of total body weight, preferably from about 0.1to 30 mg/kg, more preferably from about 0.2 mg to 15 mg. The dailyparenteral dosage regimen about 0.01 to about 80 mg/kg of total bodyweight, preferably from about 0.1 to about 30 mg/kg, and more preferablyfrom about 0.2 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such-optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of Formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

[0236] The novel compounds of Formula (I) may also be used inassociation with the veterinary treatment of mammals, other than humans,in need of inhibition of cytokine inhibition or production. Inparticular, cytokine mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section, but in particular viralinfections. Examples of such viruses include, but are not limited to,lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections,such as but not limited to feline immunodeficiency virus (FIV), bovineimmunodeficiency virus, or canine immunodeficiency virus or otherretroviral infections.

[0237] The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

[0238] The cytokine-inhibiting effects of compounds of the presentinvention were determined by the following in vitro assays:

[0239] Interleukin-1 (IL-1)

[0240] Human peripheral blood monocytes are isolated and purified fromeither fresh blood preparations from volunteer donors, or from bloodbank buffy coats, according to the procedure of Colotta et al, JImmunol, 132, 936 (1984). These monocytes (1×10⁶) are plated in 24-wellplates at a concentration of 1-2 million/ml per well. The cells areallowed to adhere for 2 hours, after which time non-adherent cells areremoved by gentle washing. Test compounds are then added to the cellsfor 1 h before the addition of lipopolysaccharide (50 ng/ml), and thecultures are incubated at 37° C. for an additional 24 h. At the end ofthis period, culture supernatants are removed and clarified of cells andall debris. Culture supernatants are then immediately assayed for IL-1biological activity, either by the method of Simon et al., J. Immunol.Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL-2, in concertwith A23187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) (ELISA assay).

[0241] Tumour Necrosis Factor (TNF):

[0242] Human peripheral blood monocytes are isolated and purified fromeither blood bank buffy coats or plateletpheresis residues, according tothe procedure of Colotta, R. et al., J Immunol, 132(2), 936 (1984). Themonocytes are plated at a density of 1×10⁶ cells/ml medium/well in24-well multi-dishes. The cells are allowed to adhere for 1 hour afterwhich time the supernatant is aspirated and fresh medium (1 ml,RPMI-1640, Whitaker Biomedical Products, Whitaker, Calif.) containing 1%fetal calf serum plus penicillin and streptomycin (10 units/ml) added.The cells are incubated for 45 minutes in the presence or absence of atest compound at 1 nM-10 mM dose ranges (compounds are solubilized indimethyl sulfoxide/ethanol, such that the final solvent concentration inthe culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol). Bacteriallipopoly-saccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) isthen added (100 ng/ml in 10 ml phosphate buffered saline) and culturesincubated for 16-18 hours at 37° C. in a 5% CO₂ incubator. At the end ofthe incubation period, culture supernatants are removed from the cells,centrifuged at 3000 rpm to remove cell debris. The supernatant is thenassayed for TNF activity using either a radio-immuno or an ELISA assay,as described in WO 92/10190 and by Becker et al., J Immunol, 1991, 147,4307.

[0243] IL-1 and TNF inhibitory activity does not seem to correlate withthe property of the compounds of Formula (I) in mediating arachidonicacid metabolism inhibition. Further the ability to inhibit production ofprostaglandin and/or leukotriene synthesis, by nonsteroidalanti-inflammatory drugs with potent cyclooxygenase and/or lipoxygenaseinhibitory activity does not mean that the compound will necessarilyalso inhibit TNF or IL-1 production, at non-toxic doses.

[0244] In vivo TNF Assay:

[0245] While the above indicated assay in an in vitro assay, thecompounds of Formula (I) may also be tested in an in vivo system such asdescribed in:

[0246] (1) “Differentiation In Vivo of Classical Non-SteroidalAntiinflammatory Drugs from Cytokine Suppressive Antiinflammatory Drugsand Other Pharmacological Classes Using Mouse Tumour Necrosis FactorAlpha Production”, Griswold et al., Drugs Under Exp. and Clinical Res.,XIX (6), 243-248 (1993); or in

[0247] (2) Boehm, et al., 1-substituted 4-aryl-5-pyridinylimidazoles—anew class of cytokine suppressive drugs with low 5-lipoxygenase andcyclooxygenase inhibitory potency. Journal Of Medicinal Chemistry 39,3929-3937 (1996) whose disclosures are incorporated by reference hereinin their entirety.

[0248] Interleukin-8 (IL-8):

[0249] Primary human umbilical cord endothelial cells (HUVEC) (CellSystems, Kirland, Wash.) are maintained in culture medium supplementedwith 15% fetal bovine serum and 1% CS-HBGF consisting of AFGF andheparin. The cells are then diluted 20-fold before being plated (250 μl)into gelating coated 96-well plates. Prior to use, culture medium arereplaced with fresh medium (200 μl). Buffer or test compound (25 μl, atconcentrations between 1 and 10(1M) is then added to each well inquadruplicate wells and the plates incubated for 6 h in a humidifiedincubator at 37° C. in an atmosphere of 5% CO₂. At the end of theincubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data is presented as mean value (ng/ml) ofmultiple samples based on the standard curve. IC₅₀'s where appropriateare generated by non-linear regression analysis.

[0250] Cytokine Specific Binding Protein Assay

[0251] A radiocompetitive binding assay was developed to provide ahighly reproducible primary screen for structure-activity studies. Thisassay provides many advantages over the conventional bioassays whichutilize freshly isolated human monocytes as a source of cytokines andELISA assays to quantify them. Besides being a much more facile assay,the binding assay has been extensively validated to highly correlatewith the results of the bioassay. A specific and reproducible cytokineinhibitor binding assay was developed using soluble cystosolic fractionfrom THP.1 cells and a radiolabeled compound. Patent Application U.S.Ser. No. 08/123175 Lee et al., filed September 1993, USSN; Lee et al.,PCT 94/10529 filed Sep. 16, 1994 and Lee et al., Nature 300, n(72),739-746 (December 1994) whose disclosures are incorporated by referenceherein in its entirety describes the above noted method for screeningdrugs to identify compounds which interact with and bind to the cytokinespecific binding protein (hereinafter CSBP). However, for purposesherein the binding protein may be in isolated form in solution, or inimmobilized form, or may be genetically engineered to be expressed onthe surface of recombinant host cells such as in phage display system oras fusion proteins. Alternatively, whole cells or cytosolic fractionscomprising the CSBP may be employed in the screening protocol.Regardless of the form of the binding protein, a plurality of compoundsare contacted with the binding protein under conditions sufficient toform a compound/ binding protein complex and compound capable offorming, enhancing or interfering with said complexes are detected.

[0252] CSBP/p38 Kinase Assay:

[0253] This assay measures the CSBP/p38-catalyzed transfer of ³²P from[a-³²P]ATP to threonine residue in an-epidermal growth factor receptor(EGFR)-derived peptide (T669) with the following sequence:KRELVEPLTPSGEAPNQALLR (residues 661-681). (See Gallagher et al.,“Regulation of Stress Induced Cytokine Production by PyridinylImidazoles: Inhibition of CSBP Kinase”, BioOrganic & MedicinalChemistry, 1997, 5, 49-64).

[0254] Reactions were carried in round bottom 96 well plate (fromCorning) in a 30 ml volume. Reactions contained (in finalconcentration): 25 mM Hepes, pH 7.5; 8 mM MgCl₂; 0.17 mM ATP (theKm_([ATP]) of p38 (see Lee et al., Nature 300, n72 pg. 639-746 (December1994)); 2.5 uCi of [g-32P]ATP; 0.2 mM sodium orthovanadate; 1 mM DTT;0.1% BSA; 10% glycerol; 0.67 mM T669 peptide; and 2-4 nM ofyeast-expressed, activated and purified p38. Reactions were initiated bythe addition of [gamma-32P]Mg/ATP, and incubated for 25 min. at 37° C.Inhibitors (dissolved in DMSO) were incubated with the reaction mixtureon ice for 30 minutes prior to adding the ³²P-ATP. Final DMSOconcentration was 0.16%. Reactions were terminated by adding 10 ul of0.3 M phosphoric acid, and phosphorylated peptide was isolated from thereactions by capturing it on p81 phosphocellulose filters. Filters werewashed with 75 mM phosphoric acids, and incorporated 32P was quantifiedusing beta scintillation counter. Under these conditions, the specificactivity of p38 was 400-450 pmol/pmol enzyme, and the activity waslinear for up to 2 hr of incubation. The kinase activity values wereobtained after subtracting values generated in the absence of substratewhich were 10-15% of total values.

[0255] Exemplified compounds herein of Examples 2 to 18, and 20 to 22have all demonstrated positive inhibitory activity of an IC₅₀ of <50uMin this kinase assay. The compound of Example 19 was not tested.

[0256] Prostoglandin Endoperoxide Synthase-2 (PGHS-2) Assay:

[0257] The following assay describes a method for determining theinhibitory effects of compounds of Formula (I) on human PGHS-2 proteinexpression in LPS stimulated human monocytes.

[0258] Method:

[0259] Human peripheral blood monocytes were isolated from buffy coatsby centrifugation through Ficoll and Percoll gradients. Cells wereseeded at 2×10⁶/well in 24 well plates and allowed to adhere for 1 hourin RPMI supplemented with 1% human AB serum, 20 mM L-glutamine,Penicillin-Streptomycin and 10 mM HEPES. Compounds were added at variousconcentrations and incubated at 37° C. for 10 minutes. LPS was added at50 ng/well (to induce enzyme expression) and incubated overnight at 37°C. The supernatant was removed and cells washed once in cold PBS. Thecells were lysed in 100l of cold lysis buffer(50 mM Tris/HCl pH 7.5, 150mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300ug/ml DNAse,0.1% TRITON X-100, 1 mM PMSF, 1 mM leupeptin, 1 mM pepstatin). Thelysate was centrifuged (10,000× g for 10 min. at 4° C.) to remove debrisand the soluble fraction was subjected to SDS PAGE. analysis (12% gel).Protein separated on the gel were transferred onto nitrocellulosemembrane by electrophoretic means for 2 hours at 60 volts. The membranewas pretreated for one hour in PBS/0.1% Tween 20 with 5% non-fat drymilk. After washing 3 times in PBS/Tween buffer, the membrane wasincubated with a 1:2000 dilution of a monospecific antiserum to PGHS-2or a 1:1000 dilution of an antiserum to PGHS-1 in PBS/Tween with 1% BSAfor one hour with continuous shaking. The membrane was washed 3× inPBS/Tween and then incubated with a 1:3000 dilution of horseradishperoxidase conjugated donkey antiserum to rabbit Ig (Amersham) inPBS/Tween with 1% BSA for one hour with continuous shaking. The membranewas then washed 3× in PBS/Tween and the ECL immunodetection system(Amersham) was used to detect the level of expression of prostaglandinendoperoxide synthases-2.

[0260] Results:

[0261] The following compounds were tested and found to be active inthis assay (i.e., inhibited LPS induced PGHS-2 protein expression inrank order potency similar to that for inhibiting cytokine production asnoted in assays indicated):6-(4-Fluoro-phenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo[2,1-b]thiazole;and Dexamethasone.

[0262] Several compounds were tested and found to be inactive (up to 10uM):2-(4-Methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-(5H)-pyrrolo[1,2-a]imidazole;Rolipram ; phenidone and N)GA. None of these compounds tested were foundto inhibit PGHS-1 or cPLA₂ protein levels in similar experiments.

[0263] TNF-α in Traumatic Brain Injury Assay

[0264] The present assay provides for examination of the expression oftumor necrosis factor mRNA in specific brain regions which followexperimentally induced lateral fluid-percussion traumatic brain injury(TBI) in rats. Adult Sprague-Dawley rats (n=42) are anesthetized withsodium pentobarbital (60 mg/kg, i.p.) and subjected to lateralfluid-percussion brain injury of moderate severity (2.4 atm.) centeredover the left temporaparietal cortex (n=18), or “sham” treatment(anesthesia and surgery without injury, n=18). Animals are sacrificed bydecapitation at 1, 6 and 24 hr. post injury, brains removed, and tissuesamples of left (injured) parietal cortex (LC), corresponding area inthe contralateral right cortex (RC), cortex adjacent to injured parietalcortex (LA), corresponding adjacent area in the right cortex (RA), lefthippocampus (LH) and right hippocampus (RH) are-prepared. Total RNA isisolated and Northern blot hybridization is performed and quantitatedrelative to an TNF-α positive control RNA (macrophage=100%). A markedincrease of TNF-α mRNA expression is observed in LH (104±17% of positivecontrol, p<0.05 compared with sham), LC (105±21%, p<0.05) and LA (69±8%,p<0.01) in the traumatized hemisphere 1 hr. following injury. Anincreased TNF-α mRNA expression is also observed in LH (46±8%, p<0.05),LC (30±3%, p<0.01) and LA (32±3%, p<0.01) at 6 hr. which resolves by 24hr. following injury. In the contralateral hemisphere, expression ofTNF-α mRNA is increased in RH (46±2%, p<0.01), RC (4±3%) and RA (22±8%)at 1 hr. and in RH (28±11%), RC (7±5%) and RA (26±6%, p<0.05) at 6 hr.but not at 24 hr. following injury. In sham (surgery without injury) ornaive animals, no consistent changes in expression of TNF-α mRNA isobserved in any of the 6 brain areas in either hemisphere at any times.These results indicate that following parasagittal fluid-percussionbrain injury, the temporal expression of TNF-α mRNA is altered inspecific brain regions, including those of the non-traumatizedhemisphere. Since TNF-α is able to induce nerve growth factor (NGF) andstimulate the release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma.

[0265] CNS Injury Model for IL-β mRNA

[0266] This assay characterizes the regional expression ofinterleukin-1β (IL-1β) mRNA in specific brain regions followingexperimental lateral fluid-percussion traumatic brain injury (TBI) inrats. Adult Sprague-Dawley rats (n=42) are anesthetized with sodiumpentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussionbrain injury of moderate severity (2.4 atm.) centered over the lefttemporaparietal cortex (n=18), or “sham” treatment (anesthesia andsurgery without injury). Animals are sacrificed at 1, 6 and 24 hr. postinjury, brains removed, and tissue samples of left (injured) parietalcortex (LC), corresponding area in the contralateral right cortex (RC),cortex adjacent to injured parietal cortex (LA), corresponding adjacentarea in the right cortex (RA), left hippocampus (LH) and righthippocampus (RH) were prepared. Total RNA is isolated and Northern blothybridization is performed and the quantity of brain tissue IL-1β mRNAis presented as percent relative radioactivity of IL-1β positivemacrophage RNA which is loaded on same gel. At 1 hr. following braininjury, a marked and significant increase in expression of IL-1β mRNA isobserved in LC (20.0±0.7% of positive control, n=6, p<0.05 compared withsham animal), LH (24.5±0.9%, p<0.05) and LA (21.5±3.1%, p<0.05) in theinjured hemisphere, which remained elevated up to 6 hr. post injury inthe LC (4.0±0.4%, n=6, p<0.05) and LH (5.0±1.3%, p<0.05). In sham ornaive animals, no expression of IL-1β mRNA is observed in any of therespective brain areas. These results indicate that following TBI, thetemporal expression of IL-1β mRNA is regionally stimulated in specificbrain regions. These regional changes in cytokines, such as IL-1β play arole in the post-traumatic pathologic or regenerative sequelae of braininjury.

SYNTHETIC EXAMPLES

[0267] The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an argon atmosphereunless otherwise indicated.

[0268] In the Examples, all temperatures are in degrees Centigrade (°C.). Mass spectra were performed upon a VG Zab mass spectrometer usingfast atom bombardment, unless otherwise indicated. ¹H-NMR (hereinafter“NMR”) spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400spectrometer. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat.indicates a saturated solution, eq indicates the proportion of a molarequivalent of reagent relative to the principal reactant.

[0269] Flash Chromatography is run over a Merck Silica gel 60 (230-400mesh).

Example 1

[0270] Polymer-bound 2-thiopyrimidine-4-carboxaldehyde.

[0271] a) Polymer-bound 2-thiopyrimidine-4-carboxaldehyde DimethylAcetal.

[0272] Sodium 2-methylthiopyrimidine-4-carboxaldehyde dimethyl acetal(116 grams (hereinafter ‘g”), 560 millimoles (hereinafter “mmol”)) wasadded to a mixture of Merrifield resin (1.4 mmol/g, 100 g, 140 mmol) inDMF (500 milliliter (hereinafter “mL”)). After stirring at ambienttemperature for about 18 hours (hereinafter “h”), the reaction mixturewas filtered and the resin was washed successively with DMF, CH₂Cl₂ andMeOH and dried to afford a yellow-colored resin; yield 116 g (94%):MASNMR (CDCl₃) δ 8.5 (1H, pyrimidine H-6), 5.2 [1H, (MeO)₂CH—], 3.3 [6H,—(OCH ₃)₂].

[0273] b) Polymer-bound 2-thiopyrimidine-4-carboxaldehyde.

[0274] A mixture of Polymer-bound 2-thiopyrimidine-4-carboxaldehydedimethyl acetal (135 g, 189 mmol maximum) in TFA (150 mL) was heated toreflux for 18 h. The reaction mixture was cooled to ambient temperatureand filtered, washed successively with CH₂Cl₂ and 5% Et₃N in CH₂Cl₂ toafford the title material as a orangish-yellow resin; yield 107 g (85%):MASNMR δ 9.9 (1H, CHO), 8.6 (1H, pyrimidine H-6).

Example 2

[0275]1-Cyclohexyl-4-(4-fluorophenyl)-5-[(2-phenylamino)pyrimidin-4-yl]imidazole.

[0276] a) Polymer-bound2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imine.

[0277] A mixture of Polymer-bound 2-thiopyrimidine-4-carboxaldehyde (5.0g, 7.0 mmol maximum) and cyclohexylamine (1.6 g, 14 mmol) in CH₂Cl₂ (50mL) were stirred at room temperature for about 18 h. The reactionmixture was filtered and the resin washed with CH₂Cl₂ to afford thetitle material.

[0278] b) Polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0279] A mixture of the entire sample of polymer-bound2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imine from Example 2a (7.0mmol maximum), 4-fluorophenyl-tolylsulfonomethylisocyamide (6.0 g, 21mmol), and TBD (2.9 g, 21 mmol), in CH₂Cl₂ (50 mL) were stirred at roomtemperature for 18 h. The reaction mixture was filtered and the resinwas washed successively with CH₂Cl₂, MeOH and CH₂Cl₂ to afford the titlematerial.

[0280] c) Polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole.

[0281] A mixture of polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole (1.5g, 2.1 mmol maximum) and 3-peroxybenzoic acid (>95%, 0.54 g, 3.2 mmol)in CH₂Cl₂ (30 mL) were stirred at room temperature for 18 h. Thereaction mixture was filtered and washed with CH₂Cl₂ to afford the titlematerial.

[0282] d)1-Cyclohexyl-4-(4-fluorophenyl)-5-[(2-phenylamino)pyrimidin-4-yl]imidazole.

[0283] Trimethyl aluminum (2M in tol, 1.0 mL, 2.1 mmol) was added to asuspension of aniline hydrochloride (0.27 g, 2.1 mmol) in toluene (10mL). The reaction mixture was stirred for 1 h at rt. Polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole(0.50 g, 0.70 mmol maximum) was added and the mixture was heated to 90°C. for 18 h. After cooling to ambient temperature, the reaction mixturewas poured into CH₂Cl₂ containing silica gel. After bubbling had ceased,the mixture was filtered and the filtrate washed successively withCH₂Cl₂, 2% MeOH in CH₂Cl₂ and 4% CH₂Cl₂. Filtrates-containingproduct-were concentrated and the-residue was further purified by vacuumfiltration through silica eluting successively with 25%, 33% and 50%EtOAc/hexanes to afford the title compound as a chromatographically purered foam; yield 0.057 g (20% overall). Trituration with ether afforded alight pink solid: ESMS m/z=414 (M⁺+H).

Example 3

[0284]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2[N-(3-morpholino)propyl]amino]pyrimidin-4yl]imidazole.

[0285] A mixture of polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole(1.0 g, 1.4 mmol maximum), 4-(3-aminopropyl)-morpholine (0.61 mL, 0.60g, 4.2 mmol) in THF was stirred at room temperature for 18 h. Thereaction mixture was filtered and the resin washed with THF. Thecombined filtrates were concentrated and the residue was vacuum filteredthrough a pad of silica gel eluting successively with 2% and 4% MeOH inCH₂Cl₂. Fractions containing product were concentrated and the residuewas triturated with ether to afford the title compound as an off-whitesolid; yield 0.17 g (26% overall): ESMS m/z=465 (M⁺+H).

Example 4

[0286]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(2-imidazol-4-yl)ethyl]amino]pyrimidin-4-yl]imidazole.

[0287] Following the procedure of Example 3 except substitutinghistamine for 4-(3-aminopropyl)morpholine afforded the title compound asan off-white solid in 14% overall yield: ESMS m/z=432 (M⁺+H).

Example 5

[0288]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3-pyridyl)methyl]amino]pyrimidin-4-yl]imidazole.

[0289] Following the procedure of Example 3 except substituting3-aminomethypyridine for 4-(3-aminopropyl)morpholine afforded the titlecompound as an off-white solid in 10% overall yield: ESMS m/z=429(M⁺+H).

Example 6

[0290]1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3,3-diphenyl)propyl]amino]pyrimidin-4-yl]imidazole.

[0291] Following the procedure of Example 3 except substituting3,3-diphenylpropylamine for 4-(3-aminopropyl)morpholine afforded thetitle compound as a white solid in 12% overall yield: ESMS m/z=532(M⁺+H).

Example 7

[0292](+/−)-1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(1-methyl-3-phenyl)propyl]amino]pyrimidin-4-yl]imidazole.

[0293] Following the procedure of Example 3 except substituting1-methyl-3-phenyl propylamine for 4-(3-aminopropyl)morpholine affordedthe title compound as a light yellow oil in 17% overall yield: ESMSm/z=532 (M⁺+H). The free base was dissolved in MeOH and an excess of 3NHCl was added. The solution was concentrated and the residue wassubjected to high vacuum and subsequently treated with ether to afford ahygroscopic tan solid.

Example 8

[0294]N-4-[[[4-(4-Fluorophenyl)]-5-[[2-[(-trifluoromethylphenyl]amino]]pyrimidine-4-yl]imidazol-4-yl]piperdinyl-N′-[(3-trifluoromethyl)phenyl]urea.a) Polymer-bound2-thiopyrimidine-4-carboxaldehyde[4-amino-1-(ethoxycarbonyl)piperidine]imine.

[0295] Following the procedure of Example 2a except substituting4-amino-1-(ethoxycarbonyl)-piperidine for cyclohexylamine afforded thetitle material.

[0296] b) Polymer-bound1-[1-(ethoxycarbonyl)piperdin-4-yl]-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0297] Following the procedure of Example 2b except substitutingpolymer-bound2-thiopyrimidine-4-carboxaldehyde[4-amino-1-(ethoxycarbonyl)piperidine]iminefor polymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imineafforded the title material.

[0298] c) Polymer-bound1-[1-(ethoxycarbonyl)piperdin-4-yl]-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole.

[0299] Following the procedure of Example 2c except substitutingpolymer-bound1-[1-(ethoxycarbonyl)piperdin-4-yl]-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazolefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazoleafforded the title material

[0300] d)N-4-[[[4-(4-Fluorophenyl)]-5-[[2-[(3-trifluoromethyl)phenyl]-aminol]pyrimidine-4-yl]imidazol-4-yl]piperidinyl-N′-[(3-trifluoromethyl)phenyl]urea.

[0301] The reaction was conducted in a manner analogous to Example 2dexcept substituting polymer-bound1-[1-(ethoxycarbonyl)piperdin-4-yl]-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazolefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazoleexcept the work-up was modified in the following manner: The cooledreaction mixture was poured into aqueous. NaOH (2.5 N), the layers wereseparated and the organic phase was washed with 2 times with H₂O and thelayers were separated. The organic phase was filtered to remove anyremaining resin and the solvents were evaporated under reduced pressure.The residue was purified by vacuum filtration through a pad of silicagel eluting with 2% MeOH in CH₂Cl₂. Concentration of fractionscontaining only product were concentrated and the residue was trituratedwith ether to afford the title compound as an off-white solid in 26%overall yield: ESMS m/z=670 (M⁺+H).

Example 9

[0302]N-[2-[4-(4-fluorophenyl)-5-[[2-(3,4-dichlorobenzyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamide.a) Polymer-bound2-thiopyrimidine-4-carboxaldehyde[[3-(t-butyloxycarbonyl)aminolethyl]imine.

[0303] Following the procedure of Example 2a except substituting2-(t-butyloxy-carbonylamino)ethylamine for cyclohexylamine afforded thetitle material.

[0304] b) Polymer-bound1-[2-(t-butyloxycarbonylamino)ethyl]-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0305] Following the procedure of Example 2b except substitutingpolymer-bound2-thiopyrimidine-4-carboxaldehyde[[3-(t-butyloxycarbonyl)amino]ethyl]iminefor polymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imineafforded the title material.

[0306] c) Polymer-bound1-(2-aminoethyl)-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0307] Polymer-bound1-[2-(t-butyloxycarbonylamino)ethyl]-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazolewas stirred for 18 h at rt. The reaction mixture was filtered and theresin was washed successively with CH₂Cl₂ and 5% Et₃N in CH₂Cl₂ toafford the title material.

[0308] d) Polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(thio)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamide.

[0309] 3,4-Dimethoxybenzoyl chloride (2.7 g, 13 mmol) was added to amixture of polymer-bound1-(2-aminoethyl)-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole(1.9 g, 2.7 mmol maximum), Et₃N (1.8 mL, 1.3 g, 13 mmol) in CH₂Cl₂ (100mL). The reaction mixture was stirred for 18 h, filtered and washedsuccessively with CH₂Cl₂, MeOH and CH₂Cl₂ to afford the title material.

[0310] e) Polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(sulfonyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3.4-dimethoxybenzamide.

[0311] Following the procedure of Example 2c except substitutingpolymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(thio)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamidefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazoleafforded the title material.

[0312] f)N-[2-[4-(4-fluorophenyl)-5-[[2-(3,4-dichlorobenzyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamide.

[0313] 3,4-Dichlorobenzylamine (0.36 mL, 0.48 g, 2.7 mmol) was added toa mixture of polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(sulfonyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamidein toluene (15 mL). The reaction mixture was heated to 90° C. for 18 h.Polymer-bound 2-thiopyrimidine-4-carboxaldehyde (1.9 g, 2.7 mmol) wasadded and the mixture was stirred for an additional 4 h to remove excess3,4-dichlorobenzylamine. The reaction mixture was poured directlythrough a pad of silica gel eluting successively with 1%, 2% and 4% MeOHin CH₂Cl₂. Fractions containing product were combined and the solventevaporated. The residue was triturated with ether to afford an off-whitesolid; yield 0.045 g (8% overall): ESMS m/z=622 (M⁺+H).

Example 10

[0314]N-[2-[4-(4-Fluorophenyl)-5-[[2-(4-methoxybenzylamino)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide.a) Polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(thio)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide.

[0315] Following the procedure of Example 9d except substitutingmethoxyacetyl chloride for 3,4-dimethoxybenzoyl chloride afforded thetitle material.

[0316] b) Polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(sulfonyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide.

[0317] Following the procedure of Example 2c except substitutingpolymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(thio)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamidefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazoleafforded the title material.

[0318] c)N-[2-[4-(4-Fluorophenyl)-5-[[2-(4-methoxybenzylamino)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide.

[0319] Following the procedure of Example 9f except substituting4-methoxybenzylamine for 3,4-dichlorobenzylamine and polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(sulfonyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamidefor polymer-boundN-[2-[4-(4-fluorophenyl)-5-[2-(sulfonyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamideafforded the title material in 24% yield: ESMS m/z=491 (M⁺+H).

Example 11

[0320]1-Isopropyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazolea) Polymer-bound 2-thiopyrimidine-4-carboxaldehyde(iso-propyl)imine.

[0321] Following the procedure of Example 2a except substitutingiso-propylamine for cyclohexylamine afforded the title material.

[0322] b) Polymer-bound1-isopropyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0323] Following the procedure of Example 2b except substitutingpolymer-bound 2-thiopyrimidine-4-carboxaldehyde(iso-propyl)imine forpolymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imineafforded the title material.

[0324] c) Polymer-bound1-isopropyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole.

[0325] Following the procedure of Example 2c except substitutingpolymer-bound1-isopropyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole forpolymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazoleafforded the title material

[0326] d)1-Isopropyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole

[0327] The reaction was conducted in a manner analogous to Example 2dexcept substituting polymer-bound1-isopropyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazolefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole:ESMS m/z=374 (MH)⁺

Example 12

[0328]1-Cyclopentyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazolea) Polymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclopentyl)imine.

[0329] Following the procedure of Example 2a except substitutingcyclopentylamine for cyclohexylamine afforded the title material.

[0330] b) Polymer-bound1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole.

[0331] Following the procedure of Example 2b except substitutingpolymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclopentyl)imine forpolymer-bound 2-thiopyrimidine-4-carboxaldehyde(cyclohexyl)imineafforded the title material.

[0332] c) Polymer-bound1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole.

[0333] Following the procedure of Example 2c except substitutingpolymer-bound1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazole forpolymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-thio)pyrimidin-4-yl]imidazoleafforded the title material

[0334] d)1-Cyclopentyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole

[0335] The reaction was conducted in a manner analogous to Example 2dexcept substituting polymer-bound1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazolefor polymer-bound1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole:ESMS m/z=400 (MH)⁺

Example 13

[0336] a)1-[(1-t-butoxycarbonyl)-4-piperidinyl]-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)amino]pyrimidin-4-yl]imidazole

[0337] Trimethylaluminum (2M in toluene, 2.9 mL, 5.8 mmol) was added toa stirred solution of 2-methyl-4-fluoroaniline (0.483 g, 3.5 mmol) intoluene (8 mL) at ambient temperature. Stirring was continued until gasevolution ceased (˜1 h) and1-[(1-t-butoxycarbonyl)-4-piperidinyl]-4-(4-fluorophenyl)-5-{2-methysulfinylpyrimidin-4-yl]imidazole(0.485 g, 1.0 mmol) was added. The resulting solution was stirred for 2h at 23° and poured into a slurry of silica gel in CH₂Cl₂. The solidswere removed by filtration and washed with 10% MeOH in CH₂Cl₂. Thecombined filtrates were concentrated and the residue was purified byflash chromatography eluting with 0-2% MeOH in CH₂Cl₂ to afford thetitle compound as a white solid: yield 0.452 g (82%): ESMS m/z=547(M⁺+H).

[0338] b)1-(4-piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)amino]-pyrimidin-4-yl]imidazole

[0339] The product of the preceding example (285 mg, 0.52 mmol) and TFA(10 mL) were combined at 23°, stirred 40 min. and the resulting yellowsolution was concentrated. The residue was dissolved in EtOAc (75 mL)and washed with 10% aqueous NaOH, dried (Na₂SO₄) and concentrated to ca10 mL. Crystals formed on standing and slow cooling to 40. Filtrationafforded 187 mg (80%). ESP+ MS m/z 447(MH⁺).

Example 14

[0340]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-5-fluorophenyl)amino]pyrimidin-4-yl]imidazole

[0341] Following the procedure of example 13 except using2-methyl-5-fluoroaniline the title compound was obtained as a whitesolid. ESP+ MS m/z 447(MH⁺).

Example 15

[0342]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-2-(2,6-dimethylphenyl)amino]pyrimidin-4-yl]imidazole

[0343] Following the procedure of example 13 except using 2,6-dimethylaniline the title compound was obtained as a white solid. ESP+ MS m/z443(MH⁺).

Example 16

[0344]1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenyl)amino]pyrimidin-4-yl]imidazole

[0345] Following the procedure of example 13 except using2-methylaniline the title compound was obtained as a white solid. ESP+MS m/z 429(MH⁺).

[0346] Using analogous procedures to those indicated above, thefollowing compounds have also been synthesized:

Example 17

[0347]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;MS ES+=426 (MH⁺).

Example 18

[0348]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenylamino)-pyrimidin-4-yl]imidazole;MS ES+=444 (MH⁺).

Example 19

[0349]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-methylphenylamino)-pyrimidin-4-yl]imidazole;MS ES+=440 (MH⁺).

Example 20

[0350]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenylamino)pyrimidin-4-yl]imidazole;MS ES+=440 (MH⁺).

Example 21

[0351]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenylamino)pyrimidin-4-yl]imidazol;MS ES+=454 (MH⁺).

Example 22

[0352]1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-2-morpholinylphenylamino)-pyrimidin-4-yl]imidazoleMS ES+=511 (MH⁺).

Example 23

[0353] Using an alternative method of synthesis the compound of Example16 was also produced:

[0354]1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-[(2-methylphenyl)amino]pyrimidin-4-yl]imidazole

[0355] a) 2-Propylthiopyrimidine-4-carboxaldehyde Dimethyl Acetal

[0356] Charge a 1 Liter (hereinafter “L”) 3-necked flask equipped with astir bar, thermometer, 100 mL addition funnel and reflux condensor withN,N-dimethylformamide dimethyl acetal (88.7 g, 98.9 mL, 700 mmol) andpyruvaldehyde dimethyl acetal (85.3 g, 86.8 mL, 700 mmol) and heat in anoil bath at 110° for about 3 to 4 hours. Cool the solution to 85° andadd thiourea (48.9 g, 636.4 mmol) and NaOMe (25 wt % in MeOH, 151.2 g,160 mL, 700 mmol) and stir at 85° for about 3 to 4 h. Cool the solutionto 65° and charge 1-bromoropane (86.9 g, 64.4 mL, 700 mmol) to theaddition funnel and add slowly over 10-15 min to the reaction, bringingthe solution to a mild reflux. After 1 h, add 100 mL of EtOAC to thereaction and bring the oil bath temperature to 95°. Replace the refluxcondensor with a distillation head and distill 150-200 mL of solventfrom the reaction. Add an additional 400 mL of EtOAc and 120 mL of H₂Oand stir at 50° about 5 minutes. Transfer to a separatory funnel andseparate the aqueous phase. Add 60 mL of H₂O, agitate, and separate theaqueous phase. A sample was concentrated to give a yellow oil: ¹H NMR(300 MHz, CDCl3) d 8.53 (1H, d, J=5.0 Hz), 7.16 (1H, d, J=5.0 Hz), 5.17(1H, s), 3.42 (3H, s), 3.14 (2H, t, J=7.3 Hz), 1.76 (2H, m), 1.05 (3H,t, J=7.3 Hz).

[0357] b) 2-Propylthiopyrimidine-4-carboxaldehyde

[0358] The product of example 1(a) (10.0 g, 50 mmol), and 3 N HCl (42mL, 126 mmol) were combined and stirred at 48° C. for 16 h, cooled to23° C., combined with EtOAc (200 mL) and made basic by the addition ofsolid Na₂CO₃ (12.6 g, 150 mmol). The aqueous phase was extracted withEtOAc (4×150 mL, dried (Na₂SO₄), concentrated and the residue wasfiltered through a pad of silica (ca 150 mL) with CH₂Cl₂ to afford 7.49g (97%) of the title compound ¹H NMR (400 MHz, CDCl₃): δ 9.95 (s, 1H),8.78 (d, 1H), 7.45 (d, 1H), 3.21 (t, 2H), 1.82 (m, 2H), 1.1 (t, 3H).

[0359] c) 1-t-Butoxycarbonyl-4-aminopiperidine

[0360] 1-t-Butoxycarbonyl piperidine-4-one (commercially available fromLancaster Chem) (39.9 g, 0.20 mol), THF (150 mL), H₂O (300 mL), and HNOHHCl (55.2, 0.80 mol) were dissolved together and Na₂CO₃ (55.2 g, 0.53mol) was added in small portions. The mixture was stirred at 23° C. for14 h, most of the THF was evaporated in vacuo, adjusted to pH>10 with50% aq NaOH, extracted with EtOAc(5×50 mL) and concentrated to a whitefoam. Triturated with hexane, filtered and the solid was dried in vacuoto afford 40.31 g.

[0361] The above residue was dissolved in EtOH (abs) (1 L) and Raney Ni(50 mL of a slurry in EtOH) was added and the mixture was reduced underH₂ (50 psi) for 3.5 h. The catalyst was filtered off and washed withEtOH to afford. Concentration afforded 38.4 g (96% overall) of the titlecompound as a colorless oil which solidified to a white solid uponstanding at −20 C.

[0362] d) 2-Propylthiopyrimidine-4-carboxaldehyde[1-t-butoxycarbonyl-4-aminopiperidine] Imine

[0363] The product of the previous step (6.72 g, 33.6 mmol), MgSO₄ (ca0.5 g), the product of example 1(b) (5.31 g, 29.2 mmol), and CH₂Cl₂ (30mL) were combined and stirred at 23° C. for 16 h. Filtration andconcentration of the filtrate afforded the title compound as a yellowoil. ¹H NMR (CDCl₃): d 8.56 (d, 1), 8.26 (s, 1), 7.57 (d, 1), 4.05 (m,2), 3.52 (m, 1), 3.18 (t, 2H), 3.00 (m, 2), 1.75 (m, 7), 1.48 (s, 9),1.05 (t, 3H).

[0364] e) 4-Fluorophenyl-tolylsulfonomethylformamide

[0365] To a suspension of p-toluenesulfinic acid sodium salt (30 g) inH₂O (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwiseaddition of conc HCl (15 mL). After stirring 5 min, the organic phasewas removed and the aqueous phase was extracted with methyl t-butylether. The organic phase was dried (Na₂SO₄) and concentrated to neardryness. Hexane was added and the resulting precipitate collected toafford p-toluenesulfinic acid; yield 22 g. p-Toluenesulfinic acid (22 g,140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL,503 mmol) and camphor sulphonic acid (4 g, 17.3 mmol) were combined andstirred at 60° C. 18 h. The resulting solid was broken up and stirredwith a mixture of MeOH (35 mL) and hexane (82 mL) then filtered. Thesolid was resuspended in MeOH/hexanes (1:3, 200 mL) and stirredvigorously to break up the remaining chunks. Filtration afforded thetitle compound (27 g, 62% yield): ¹H NMR (400 MHz, CDCl₃) d 8.13 (s,1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d,1H), 2.45 (s, 3H).

[0366] f) 4-Fluorophenyl-tolylsulfonomethylisocyamide

[0367] 4-Fluorophenyl-tolylsulfonomethylformamide (2.01 g, 6.25 mmol) inDME (32 mL) was cooled to −10° C. POCl₃ (1.52 mL, 16.3 mmol) was addedfollowed by the dropwise addition of triethyl amine (4.6 mL, 32.6 mmol)in DME (3 mL) keeping the internal temperature below −5° C. The mixturewas gradually warmed to ambient temperature over 1 h, poured into H₂Oand extracted with EtOAc. The organic phase was washed with sat aqNaHCO₃, dried (Na₂SO₄), and concentrated. The resulting residue wastriturated with petroleum ether and filtered to afford the titlecompound (1.7 g, 90% yield): ¹H NMR (CDCl₃) d 7.63 (d, 2H), 7.33 (m,4H), 7.10 (t, 2H), 5.60 (s, 1H), 2.50 (s, 3H).

[0368] g)1-[(1-t-Butoxycarbonyl)piperidin-4-yl]-4-(4-fluorophenyl)-5-[(2-propylthio(pyrimidin-4-yl)]imidazole

[0369] The product of example 1(d) and the product of the previousexample (9.41 g, 32.6 mmol), DMF (64 mL) and K₂CO₃ (4.43 g, 32.4 mmol)were combined and stirred for 2 days, diluted with Et₂O and filtered.The solid was washed with Et₂O and the filtrate was concentrated to ayellow solid. Trituration of the solid with Et₂O, filtration and washingwith more Et₂O and drying in vacuo afforded 9.07 g of the title compoundas a white solid (62% from the product of example l(b)). MS ES+ m/z=498(MH⁺).

[0370] h)1-[(1-t-Butoxycarbonyl)piperidin-4-yl]-4-(4-fluorophenyl)-5-[(2-propylsulfinyl(pyrimidin-4-yl)]imidazole

[0371] The product of the previous example (9.07 g, 19.3 mmol),dissolved in THF (250 mL) was cooled to −10° C. and OXONE (14.2 g, 23.2mmol) in H₂O (250 mL) was added dropwise (T<100). The resulting mixturewas stirred at 23° C. for 1 h, combined with ice (100 mL) and CH₂Cl₂(700 mL) shaken and the aqueous was separated. The organic phase waswashed with brine (100 mL), dried (Na₂SO₄), concentrated and dried invacuo to afford 8.27 g (84%) of the title compound as a white foam. MSES+ m/z=514 (MH⁺). i)1-[(1-t-Butoxycarbonyl)piperidin-4-yl)-4-(4-Fluorophenyl)-5-[(2-methylphenyl)amino]pyrimidin-4-yl]imidazole

[0372] o-Toluidine (0.19 mL, 175 mmol) and toluene (4 mL) were dissolvedtogether, cooled to 40 and treated dropwise with tri-methylaluminum intoluene (2M) (0.875 mL, 1.75 mmol), stirred 1.5 h at 23° and then theproduct of the previous step (243 mg, 0.5 mmol) was added in oneportion. Stirred 1.5 h and diluted with EtOAc and washed with 10% aqNaOH (2×), dried (Na₂SO₄), concentrated and the residue was flashchromatographed over silica with 0-2% MeOH in CH₂Cl₂) to afford 250 mg(95%) of a white foam. MS ES+=529 (MH⁺).

[0373] i)1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-[(2-methylphenyl)amino]pyimidin-4-yl]imidazole

[0374] The product of the previous step (249 mg, 0.47 mmol) was combinedwith TFA (10 mL) and the resulting solution was stirred for 15 min, theTFA was evaporated in vacuo, the residue was dissolved in EtOAc, washedwith 10% aq NaOH, dried (NaSO₄), concentrated and crystallized fromEtOAc and hexane (1:1) to afford 84 mg (42%) of white crystals. MSES+=429 (MH⁺).

Example 24

[0375] Using an alternative method of synthesis the compound of Example13 was also produced:

[0376]1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-[2-methyl-4-fluorophenyl)amino]pyrimidin4-yl]imidazole

[0377] The title compound was prepared by the procedure of example 23except that 2-methyl-4-fluoroaniline was use as the aniline reactant. MSES+=447 (MH⁺).

Example 25

[0378] Using an alternative method of synthesis the compound of Example15 was also produced:

[0379]1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-[2,6-dimethylphenyl)amino]pyrimidin-4-yl]imidazole

[0380] The-title compound was prepared by the procedure of example 23except that 2,6-dimethylaniline was use as the aniline reactant. MSES+=443 (MH⁺).

[0381] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0382] The above description fully discloses the invention includingpreferred embodiments thereof. Modifications and improvements of theembodiments specifically disclosed herein are within the scope of thefollowing claims. Without further elaboration, it is believed that oneskilled in the are can, using the preceding description, utilize thepresent invention to its fullest extent. Therefore the Examples hereinare to be construed as merely illustrative and not a limitation of thescope of the present invention in any way. The embodiments of theinvention in which an exclusive property or privilege is claimed aredefined as follows.

What is claimed is:
 1. A compound which is:1-Cyclohexyl-4-(4-fluorophenyl)-5-[(2-phenylamino)pyrimidin-4-yl]imidazole;1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2[N-(3-morpholino)propyl]amino]pyrimidin-4-yl]imidazole;1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(2-imidazol-4-yl)ethyl]amino]pyrimidin-4-yl]imidazole;1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3-pyridyl)methyl]amino]pyrimidin-4-yl]imidazole;1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3,3-diphenyl)propyl]amino]pyrimidin-4-yl]imidazole;(+/−)-1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(1-methyl-3-phenyl)propyl]amino]pyrimidin-4-yl]imidazole;N-4-[[[4-(4-Fluorophenyl)]-5-[[2-[(3-trifluoromethyl)phenyl]amino]]pyrimidine-4-yl]imidazol-4-yl]piperdinyl-N′-[(3-trifluoromethyl)phenyl]urea;N-[2-[4-(4-Fluorophenyl)-5-[[2-(3,4-dichlorobenzyl)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-3,4-dimethoxybenzamide;N-[2-[4-(4-Fluorophenyl)-5-[[2-(4-methoxybenzylamino)pyrimidin-4-yl]-1H-imidazol-1-yl]ethyl]-ethoxyacetamide;1-Isopropyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;1-Cyclopentyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;1-[(1-t-Butoxycarbonyl)-4-piperidinyl]-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)-amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-5-fluorophenyl)amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenyl)amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenyl)amino]pyrimidin-4-yl]imidazole;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-fluorophenylamino)-pyrimidin-4-yl]imidazole;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-methylphenylamino)-pyrimidin-4-yl]imidazole;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenylamino)pyrimidin-4-yl]imidazole;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenylamino)pyrimidin-4-yl]imidazol;1-(4-Fluorophenyl)-4-(4-fluorophenyl)-5-[2-(4-2-morpholinylphenylamino)-pyrimidin-4-yl]imidazole;or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound, or pharmaceutically acceptable saltthereof, according to claim 1, and a pharmaceutically acceptable carrieror diluent.
 3. A method of treating a CSBP/RK/p38 kinase mediateddisease in a mammal in need thereof, which comprises administering tosaid mammal an effective amount of a compound according to claim
 1. 4.The method according to claim 3 wherein the disease is selected frompsoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,traumatic arthritis, rubella arthritis and acute synovitis, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, Alzheimer's disease, stroke,neurotrauma, CNS injury, restinosis, reperfusion injury, asthma, adultrespiratory distress syndrome, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcososis, bone resorptiondisease, osteoporosis, restenosis, stroke, cardiac and renal reperfusioninjury, chronic renal failure, congestive heart failure, angiogenicdiseases, thrombosis, glomerularnephritis, diabetes, graft vs. hostreaction, allograft rejection, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, multiple sclerosis, muscle degeneration,eczema, contact dermatitis, psoriasis, pyresis, sunburn, orconjunctivitis.
 5. A method of treating inflammation in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound according to claim
 1. 6. A method of treatingosteoporosis in a mammal in need thereof, which comprises administeringto said mammal an effective amount of a compound according to claim 1.7. A compound according to claim 1 which is:1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methylphenyl)amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2,6-dimethylphenyl)amino]pyrimidin-4-yl]imidazole;or1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-4-fluorophenyl)-amino]pyrimidin-4-yl]imidazole;1-Cyclohexyl-4-(4-fluorophenyl)-5-[[2-[N-(3-pyridyl)methyl]amino]pyrimidin-4-yl]imidazole;1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-[2-(2-methyl-5-fluorophenyl)amino]pyrimidin-4-yl]imidazole;1-Isopropyl-4-(4-fluorophenyl)-5-[2-phenylamino-pyrimidin-4-yl]imidazole;or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound, or pharmaceutically acceptable saltthereof, according to claim 7, and a pharmaceutically acceptable carrieror diluent.
 9. A method of treating a CSBP/RK/p38 kinase mediateddisease in a mammal in need thereof, which comprises administering tosaid mammal an effective amount of a compound according to claim
 7. 10.The method according to claim 9 wherein the disease is selected frompsoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,traumatic arthritis, rubella arthritis and acute synovitis, rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic condition, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, Alzheimer's disease, stroke,neurotrauma, CNS injury, restinosis, reperfusion injury, asthma, adultrespiratory distress syndrome, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcososis, bone resorptiondisease, osteoporosis, restenosis, cardiac and renal reperfusion injury,thrombosis, glomerularnephritis, diabetes, graft vs. host reaction,allograft rejection, inflammatory bowel disease, Crohn's disease,ulcerative colitis, multiple sclerosis, muscle degeneration, eczema,contact dermatitis, psoriasis, pyresis, sunburn, or conjunctivitis. 11.A method of treating inflammation in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundaccording to claim
 7. 12. A method of treating osteoporosis in a mammalin need thereof, which comprises administering to said mammal aneffective amount of a compound according to claim
 7. 13. A compound ofthe formula

R₁ is 4-pyridazinyl, or a 1,2,4-triazin-5-yl ring, which ring issubstituted with NLHR_(a) and optionally substituted with an additional,independent, substituent of C₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆alkyl substituted amino, N(R₁₀)C(O)R_(b) or NHR_(a); R_(a) is aryl,arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl,heteroarylC₁₋₆alkyl, wherein each of these moieties may be optionallysubstituted; R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl; R₄ is phenyl, naphth-1-yl or naphth-2-yl, or aheteroaryl, which is optionally substituted by one or two substituents,each of which is independently selected, and which, for a 4-phenyl,4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen,cyano, nitro, C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃,S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl,(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃, NR₁₀S(O)_(m′)R₈, NR₁₀S(O)_(m),NR₇R₁₇, ZC(Z)R₃or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄; v is 0, or an integer having a value of 1 or2; m is 0, or the integer 1 or 2; m′ is an integer having a value of 1or 2, m″ is 0, or an integer having a value of 1 to 5; R₂ is(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl, heterocyclyl₁₋₁₀ alkyl, C₁₋₁₀alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl-C₁₋₁₀-alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroaryl-₁₋₁₀-alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈ (CR₁₀R₂₀)_(n)S(O)_(m), NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₀R₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉₎₋4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups may be optionallysubstituted; n is an integer having a value of 1 to 10; n′ is 0, or aninteger having a value of 1 to 10; Z is oxygen or sulfur; R₃ isheterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈; R₅ is hydrogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇, excluding the moieties —SR₅ being—SNR₇R₁₇ and —SOR₅ being —SOH; R₆ is hydrogen, a pharmaceuticallyacceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroaryl₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₁₅; R₈ is C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;R₉ is hydrogen, C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(O)₂R₁₈,optionally substituted aryl or optionally substituted aryl-C₁₋₁₄ alkyl;R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; R₁₂ is hydrogen or R₁₆; R₁₃ and R₁₄ is eachindependently selected from hydrogen or optionally substituted C₁₋₄alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄alkyl, or together with the nitrogen which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉; R₁₅ is R₁₀ orC(Z)—C₁₋₄ alkyl; R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇cycloalkyl; R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,aryl₁₋₁₀alkyl, heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl orheteroaryl₁₋₁₀ alkyl; R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
 14. Apharmaceutical composition comprising a compound, or pharmaceuticallyacceptable salt thereof, according to claim 13, and a pharmaceuticallyacceptable carrier or diluent.
 15. A method of treating a CSBP/RK/p38kinase mediated disease, in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound accordingto claim
 13. 16. The-method according to claim 15 wherein the disease isselected from psoriatic arthritis, Reiter's syndrome, rheumatoidarthritis, gout, traumatic arthritis, rubella arthritis and acutesynovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic condition, sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer'sdisease, stroke, neurotrauma, CNS injury, restinosis, reperfusioninjury, asthma, adult respiratory distress syndrome, cerebral malaria,chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis,bone resorption disease, osteoporosis, restenosis, cardiac and renalreperfusion injury, thrombosis, glomerularnephritis, diabetes, graft vs.host reaction, allograft rejection, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, multiple sclerosis, muscle degeneration,eczema, contact dermatitis, psoriasis, pyresis, sunburn, orconjunctivitis.
 17. A process of making a compound of Formula (A):

R₁ is 4-pyrimidinyl ring which ring is substituted with NHR_(a) andoptionally substituted with an additional, independent, substituent ofC₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆ alkyl substituted amino,N(R₁₀)C(O)R_(b) or NHR_(a); R_(a) is hydrogen, alkyl, optionallysubstituted alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl, wherein each of the aryl,heterocyclic and heteroaryl containing moieties may be optionallysubstituted; R_(b) is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl; R₄ is phenyl, naphth-1-yl or naphth-2-yl, or aheteroaryl, which is optionally substituted by one or two substituents,each of which is independently selected, and which, for a 4-phenyl,4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen,cyano, nitro, C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃,S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl,(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃, NR₁₀S(O)_(m′)R₈, NR₁₀S(O)_(m),NR₇R₁₇, ZC(Z)R₃or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄; v is 0, or an integer having a value of 1 or2; m is 0, or the integer 1 or 2; m′ is an integer having a value of 1or 2, m″ is 0, or an integer having a value of 1 to 5; R₂ is(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl, heterocyclyl₁₋₁₀ alkyl, C₁₋₁₀alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇ cycloalkenyl,C₅₋₇cycloalkenyl-C₁₋₁₀-alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroaryl-₁₋₁₀-alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NO₂,(CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈ (CR₁₀R₂₀)_(n)S(O)_(m), NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₁₁, (CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁,(CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)NR₁₀R₉,(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁,(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁, (CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀, 5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉₎₋4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cycloalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups may be optionallysubstituted; n is an integer having a value of 1 to 10; n′ is 0, or aninteger having a value of 1 to 10; Z is oxygen or sulfur; R₃ isheterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈; R₅ is hydrogen, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇, excluding the moieties —SR₅ being—SNR₇R₁₇ and —SOR₅ being —SOH; R₆ is hydrogen, a pharmaceuticallyacceptable cation, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroaryl₁₋₄alkyl, heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₁₅; R₈ is C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈,(CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;R₉ is hydrogen, C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl, S(O)₂R₁₈,optionally substituted aryl or optionally substituted aryl-C₁₋₁₄ alkyl;R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl; R₁₂ is hydrogen or R₁₆; R₁₃ and R₁₄ is eachindependently selected from hydrogen or optionally substituted C₁₋₄alkyl, optionally substituted aryl or optionally substituted aryl-C₁₋₄alkyl, or together with the nitrogen which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₉; R₁₅ is R₁₀ orC(Z)—C₁₋₄ alkyl; R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇cycloalkyl; R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl,aryl₁₋₁₀alkyl, heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl orheteroaryl₁₋₁₀ alkyl; R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof. whichprocess comprises a) reacting polymer bound 2-thiopyrimidine-4-yl imineof the formula:

 wherein R₂ is as defined in Formula (A) above, and P is a polymer solidsupport;  with an isonitrile of the formula:

 wherein R₄ is as defined for Formula (A) above,  to yield apolymer-bound 2-thiopyrimidinyl-imidazile of the formula:

b) wherein the polymer-bound 2-thiopyrimidinyl-imidazole of step (a) isrelease from the polymer by oxidizing the sulfur moiety to thecorresponding sulfone or sulfoxide, or a combinations thereof, of theformula:

 wherein m is 1 or 2; and c) reacting the sulfone or sulfoxide with anamine of the formula NH₂R_(a), wherein R_(a) is as defined in Formula(A), to yield a compound of Formula (A):


18. The process according to claim 17 wherein the oxidation of theimidazole to the corresponding sulfoxide or sulfone is by reaction withan organic soluble oxidant, 3-chloroperoxybenzoic acid.
 19. The processaccording to claim 17 wherein the oxidation takes place in a solventwhich swells the resin.
 20. The process according to claim 18 whereinthe cycloaddition reaction of the imine with the isonitrile is in anorganic solvent which swells the polymer resin, and includes a basewhich is soluble in this organic solvent.
 21. The process according toclaim 17 wherein the polymer bound 2-thiopyrimidine-4-yl imine is formedby reaction of a polymer-bound aldehyde of the formula:

with NH₂R₂, wherein R₂ is as defined in formula (A).
 22. The processaccording to claim 21 wherein the polymer bound aldehyde is formed byhydrolysis of a polymer-bound pyrimidine acetal of the formula:

with a strong acid.
 23. The process according to claim 22 wherein theacetal is bound to the polymer resin by reaction of a salt form of2-thiopyrimidine-4-carboxaldehyde with a suitable resin in an organicsolvent which swells the resin and dissolves the salt.
 24. A process forproducing a compound of the formula:

wherein: R₂ R_(a) cyclohexyl phenyl cyclohexyl

cyclohexyl

cyclohexyl

cyclohexyl (3,3-diphenyl)propyl cyclohexyl (1-methyl-3-phenyl)propyl

(3-trifluoromethyl)phenyl (3,4-dimethoxybenzamide 3,4-dichlorobenzylethyl ethoxyacetamide-ethyl 4-methoxybenzyl isopropyl phenyl cyclopentylphenyl (1-t-butoxycarbonyl)-4- (2-methyl-4-fluorophenyl) piperidinyl4-piperidinyl (2-methyl-4-fluorophenyl) 4-piperidinyl(2-methyl-5-fluorophenyl) 4-piperidinyl (2,6-dimethylphenyl)4-piperidinyl (2-methylphenyl) 4-fluorophenyl phenyl 4-fluorophenyl(2-methylphenyl) 4-fluorophenyl (2,6-dimethylphenyl) 4-fluorophenyl

which process comprises reacting a compound of the formula:

 with a compound of the formula:

 wherein p is 2, Ar is an unsubstituted or substituted aryl; and R_(a)and R₂ are as described above; with a base strong enough to deprotonatethe isonitrile moiety of Formula (IIa); and wherein the imine of Formula(III), is formed in situ prior to reaction with Formula (IIa); to yielda compound as defined in the table above.
 25. The process according toclaim 24 wherein the base is an amine, an amide, a carbonate, a hydride,an alkyl or aryl lithium reagent, or a mono-, di- or tribasic phosphate.26. The process according to claim 24 wherein the imine is formed insitu by reacting an aldehyde of the formula:

wherein R_(a) is as defined above, with a primary amine of the formulaR₂NH₂, wherein R₂ is as defined above.
 27. The process according toclaim 24 wherein formation of the imine in situ utilizes dehydratingconditions.
 28. The process according to claim 24 wherein the solvent isN,N-dimethyl-formamide (DMF), halogenated solvents, tetrahydrofuran(THF), dimethylsulfoxide (DMSO), an alcohol, benzene, toluene, MeCN, orDME.
 29. A process for producing a compound of the formula:

wherein: R₂ R_(a) cyclohexyl phenyl cyclohexyl

cyclohexyl

cyclohexyl

cyclohexyl (3,3-diphenyl)propyl cyclohexyl (1-methyl-3-phenyl)propyl

(3-trifluoromethyl)phenyl (3,4-dimethoxybenzamide 3,4-dichlorobenzylethyl ethoxyacetamide-ethyl 4-methoxybenzyl isopropyl phenyl cyclopentylphenyl (1-t-butoxycarbonyl)-4- (2-methyl-4-fluorophenyl) piperidinyl4-piperidinyl (2-methyl-4-fluorophenyl) 4-pipendinyl(2-methyl-5-fluorophenyl) 4-piperidinyl (2,6-dimethylphenyl)4-piperidinyl (2-methylphenyl) 4-fluorophenyl phenyl 4-fluorophenyl(2-methylphenyl) 4-fluorophenyl (2,6-dimethylphenyl) 4-fluorophenyl

which process comprises reacting a compound of the formula:

 with a compound of the formula:

 wherein R is a substituted or unsubstituted C₁₋₄ alkyl; Ar is anunsubstituted or substitued aryl; R₂ is as defined above, and p is =2; to yield a compound of the formula:

 wherein R and R₂ are as defined above; and using oxidizing conditionsto make the corresponding sulfone or sulfoxide derivative; and usingdisplacement conditions reacting the corresponding sulfone or sulfoxidederivative with the desired NH₂Ra moiety, or a metal precurser thereof,to yield a compound as defined in the table above.
 30. The processaccording to claim 29 wherein the NH₂R_(a) moiety is activated bytrimethyl aluminum to yield the aluminum salt precurser; or NH₂R_(a) isactivated by butyl lithium to yield the lithium salt precurser.